Unit 9 - Respiratory System

9.1 - Anatomy, Function, and Gas Laws

Overview

• Breathing is essential to life

• Respiratory works with cardiovascular system to supply cells with oxygen and remove CO2
Sufficient carrying capacity, and removal of CO2
• Working over short distances (diffusion) and long distance (convection)
• Upper respiratory tract: Olfaction, and speech
• Lower respiratory tract: Gas exchange

Four Processes of Respiration

1. Ventilation: Breathing air in and out. Refreshes gases. Convection.


2. External respiration: Gas exchange between alveoli and pulmonary capillaries. Diffusion.
3. Perfusion/Transport: Carries oxygenated blood from lungs to systemic circulation. External
and internal convection mechanisms. Convection.
4. Internal respiration: Gas exchange between systemic capillaries and cells. Diffusion.
Deoxygenated blood is then transported back to heart

Basic Atmospheric Conditions

• Environment impacts respiratory system

• From highest to lowest: N2 > O2 > Ar > CO2 > H2O
• Assume temperature is 37C unless indicated otherwise
• Atmospheric pressure must be taken into account
• At sea level (0 ft): 1 ATM = 760 mmHg
Roughly 100% of O2 is available’
• At mount Everest (29,000 ft): 0.32 ATM = 250 mmHg
Roughly 1% of O2 is available
• As elevation (altitude) increases, atmospheric pressure decreases. The amount of oxygen
(percentage) does not change, however available oxygen changes
• Sufficient atmospheric pressure required for respiration
People pass out at high elevations
Four Gas Laws of Respiration

1. Fick’s Law of Diffusion: Vgas = A/T * D * (P1 - P2)

2. Dalton’s Law: Pair = PO2 + PCO2 + PN2
3. Henry’s Law: [O2]Dis = S * PO2
4. Boyle’s Law: P1V1 = P2V2

Fick’s Law - Diffusion

• Random movement of molecules (in gas phase, or dissolved in water) results in net
movement from high to low concentrations

• No energy is required (passive process)

• Driving force is concentration gradient (partial pressure)
• Diffusion is fundamental in CO2, and O2

Fick’s Law - Gases

• The rate of gas transfer (Vgas) is proportional to tissue area, diffusion coefficient of the gas, and
partial pressure difference of gas on two sides of tissue. Inversely proportional to thickness.
• Vgas = A/T * D * (P1 - P2)
Vgas = Diffusion rate
A = Tissue area (units: length2)
T = Tissue thickness (units: length)
D = Diffusion coefficient of gas (units: length2/time)
P1 - P2 = Difference in partial pressure (instead of C1 - C2) (units: mmHg)
• Respiratory membranes are barriers to gases
1st barrier: Alveoli wall. External respiration
2nd barrier: Capillary wall, and plasma membrane. Internal respiration

Dalton’s Law

• Total pressure of gas mixture is equal to sum of pressure that each gas exerts independently
Pair = PO2 + PCO2 + PN2
• Dalton’s law describes how individual gas behaves when part of a mixture. Three main factors.
1. Gas mixture exerts some pressure (Ex. Atmosphere exerts partial pressure of 760 mmHg
around our body). Each gas in the mixture has an independent pressure (partial pressure)
2. Sum of the partial pressures equals total atmospheric pressure
3. Partial pressure is proportional to the percentage of gas in total mixture
• Example: Partial pressure for oxygen at sea level. 21% * 760 mmHg = 159 mmHg
• This is why altitude change causes reduced oxygen availability. Diffusion decreases when
atmospheric pressure decreases since diffusion is driven by partial pressure gradient.
Henry’s Law

• When a gas contacts liquid, it partitions into that liquid proportional to its partial pressure
• At constant temperature, amount of a gas dissolved in a type and volume of liquid is directly
proportional to the partial pressure of that gas in equilibrium with the liquid.
OR
• Solubility of a gas in a liquid at a temperature is proportional to the pressure of that gas above
the liquid
• Greater concentration of gas in mixture, them more that gas partitions into liquid phase
Solubility also matters
• Once equilibrium reached, partial pressures of a gas equal in liquid and gas phase. If
something increases partial pressure, gas enters liquid until new equilibrium reached.
• This happens in respiration. Between two membranes, and two phases.

Applying Henry’s Law

• [O2]Dis = S * PO2
[O2]Dis = Oxygen dissolved in water (units: mM)
S = Solubility (units: mM/mmHg)
PO2 = Partial pressure of oxygen (units: mmHg)
• Example: If liquid in beaker is equilibrated in 100 mmHg, then [O2]Dis equal to 0.13 mM
If liquid is 40 mmHg, then [O2]Dis equal to 0.05 mM
• As atmospheric pressure decreases, then [O2]Dis decreases
• CO2 solubility for CO2 is 20x greater than O2

Henry’s Law in a Beaker

• Putting two beakers next to each other, separated by semi-permeable membrane

ΔO2 = Concentration gradient = 0.08 mM
ΔPO2 = Partial pressure gradient = 60 mmHg
• Oxygen flows from high to low (left to right)
• Flow is proportional to ΔPO2
• Partial pressure gradient occurs during gas exchange in internal respiration
Oxygenated blood in alveoli is at higher pressure (100 mmHg)
Deoxygenated blood returned is at lower pressure (40 mmHg)
Wet gases: Partial pressures of O2 and CO2 in solutions equilibrated with wet air

• Beaker filled with water is a representation of the respiratory system (dry and wet air)
• Dry air: Bulk phase (No water vapor)
• Wet air: Water vapor present in composition of gas
• We inhale cool, dry air without water vapor. Respiratory warm and humidifies air to
approximate wet air
• PH2O = 47 mmHg
• PP for oxygen in dry air: (760) * 21% = 159 mmHg
• PP for oxygen in wet air: (760 - 47) * 21% = 149 mmHg
• In wet air, partial pressure of gases are lower
• In alveoli, PH2O is roughly 47 mmHG
Affects partial pressure

Convection enhances diffusion by producing steeper gradient across a diffusion barrier

• Convection: The bulk movement of a gas or fluid

Purpose is to produce a partial pressure gradient established by diffusion

• Large organisms couple a convection system to diffusion which creates steady flow of air
Non-microorganisms cannot meet their metabolic needs utilizing purely diffusion

• External convection system: Tubes that bring atmospheric air towards respiratory membranes.
Maximizes gas exchange by supplying bulk-phase air to gas exchange site in lungs.

• Internal convective system: Circulating blood. Maximizes O2 and CO2 flow across barrier of
gas exchange by delivering blood to the site of internal respiration.
• Diffusion is used in both internal and external respiration over short distance.
Coupling convection system to diffusion creates a relatively steady front of inspired air
• O2 Pathway: Convection —> Diffusion —> Convection —> Diffusion
Lung airways —> Alveoli —> Circulation —> Interstitial fluid —> Cell
• CO2 Pathway: Diffusion —> Convection —> Diffusion —> Convection
Cell —> Interstitial fluid —> Circulation —> Alveoli —> Lung airways
• Two pumps are needed: The heart, and air (chest wall, muscles of respiratory, air convection
passageways) pumps
• Ventilation: Moving air in and out of lungs, allows extraction of atmosphere. Ventilated with
4000 mL of air per minute, and around 250 mL of oxygen extracted.
• Convection ensures the external surface of the gas exchange barrier is in close contact with a
fluid whose composition is close to that of the bulk phase 

• Balance optimization of alveolar PO2 and PCO2 with ventilation work 

• Adult human: alveolar PO2 = 100 mmHg, and PCO2 = 40 mmHg
• Skeletal muscles allows air movement. High ventilation rates comes with metabolic cost.
Balance needed to optimize partial pressures and ATP cost of ventilation.


Clinical Correlate: Barbiturate Poisoning

• External convection system fails


• Inhibits respiratory centers of the medulla
• Alveolar PO2 falls and PCO2 rises. Partial pressure gradient collapses.
No longer able to diffuse oxygen from alveoli to plasma or offload CO2 from plasma
• Suppression of respiratory drive results in respiratory depression.
• Drugs that target air pump. Ventilation slows, and shallows
• Causes: Alcohol, benzodiazepines, opiates, sleeping pills, and any combination of them

Functional Anatomy

• Pulmonary system consists of groups of passages that filter air and transport it from the
environment and into the lungs where gas exchange occurs within alveoli (tiny air sacs)
• Two important characteristics:

1. Uses highly efficient convective systems (ventilatory and circulatory systems)
2. Reserves diffusion exclusively for short-distance movement of CO2 and O2

Key Components of Respiratory System

• Air pump which is responsible for ventilation


• Mechanisms for carrying gases (O2 and CO2) in the blood plasma

• Surface for gas exchange (alveoli)

• Circulatory system 

• Mechanism for locally regulating distribution of pulmonary ventilation and perfusion

• Mechanism for centrally (CNS) regulating ventilation

Respiratory System Divisions

• Organs in upper and lower respiratory system

Upper: Nose and nasal cavities
Lower: Pharynx and larynx, Trachea and bronchial tree, Lungs and alveoli
• Diaphragm: Major muscle of inspiration. Mass of skeletal muscle. Separates thoracic and
abdominal cavities

Conducting and Respiratory Zones

• Conducting zone: Site of convection. Conducts air to respiratory zone. Humidifies, warms,
and filters air. Hairs of nose serve as filter.
Lung components: Trachea, Bronchial tree, Bronchioles 

• Respiratory zone: Gas exchange between air and blood (external)
Lung components: Respiratory bronchioles, Alveolar sacs (Surfactant prevents collapse)
Tracheobronchial Tree

• Generation 1-10: Bronchioles with cartilage

• Generation 11-19: Bronchioles without cartilage
• Generation 20-22: Alveolar ducts
• Generation 23: Alveolar sac
• Conducting zone: 1-16. More cilia, and mucus.
• Respiratory zone: 17-23. Less cilia, and mucus.
• Cartilage ring: Surrounds branches of tracheobronchial tree to prevent collapse. Replaced by
smooth muscles and elastic fibers after generation 11.
• Respiratory bronchioles: Bronchioles with alveoli attached
• Bronchus: Stem coming off trachea, branches into bronchi, then into bronchioles
• Epithelium of trachea have cilia which trap any molecules to sweep them towards nose or
mouth to be removed by swallowing or coughing.
• Any pathogen in deeper passage requires macrophages to be removed

Bronchioles and Alveoli

• Bronchiole contain smooth muscle rings innervated by ANS. Modulates diameter, and flow.
• Alveoli contains no smooth muscle, instead there is elastic fibers which resist stretching and
facilitate recoil. Each alveoli has basket of pulmonary capillaries that surrounds it

Alveolus and Respiratory Membrane

• Alveoli structure has single epithelial layer (thin wall). Two types of cells in epithelial wall
• Type 1 pneumocytes: Very thin, used in diffusion
• Type 2 pneumocytes: Thicker, and produces surfactant. When damaged, it proliferates.
Thickness, and diffusion of membrane is compromised when healing.
• Pores in epithelium are used to equalize air pressure throughout lung
• Layers from alveoli to capillary: Surfactant —> Alveolar epithelium —> Fused basement
membranes —> Capillary endothelium —> Plasma (Total length = 0.1 - 0.5 um)
• Air velocity and aggregate cross sectional area change over generation number
At 14, x-sectional increases, and velocity decreases which maximizes gas exchange

Pulmonary & Systemic Circulations

• There are two circulations in the lungs which differ in size, origin, and function
• Pulmonary circulation: Deoxygenated blood from heart to alveoli. Sent via pulmonary
arteries which branch into pulmonary capillaries. High volume. Low pressure.
• Bronchial circulation: Oxygenated blood to tissues of lungs (except alveoli). Arteries coming
off aorta supply lungs with oxygenated blood. Low volume. High pressure.
• Rate of blood flow is equal in both pulmonary and systemic
• Alveoli receive their circulation from pulmonary capillaries, unlike rest of tissues of lungs.
• Entire systemic circulation passes pulmonary about once per minute
• Angiotensin converting enzyme high in pulmonary capillaries
• Gravity affects pulmonary, but not bronchiole circulation. Blood is non-uniform in lungs.
Blood Supply and Innervation of the Lungs

• Pulmonary plexus: Source of pulmonary innervation. Located in roots of lungs. Innervates

smooth muscle within convective airways and blood vessels
• Sympathetics —> Bronchodilation, vasoconstriction, and smooth muscle relaxation
• Parasympathetics —> Bronchoconstriction, vasodilation, and smooth muscle contraction



Blood flow to the lungs

• Pulmonary circuit: Same rate of flow as systemic. Same CO from left and right heart.
Lower pressure
• When standing, most of the blood flow is to lung base due to gravity

• During exercise, more blood flow to apex
More distribution of blood in lungs

Regional blood flow in the lungs

• Flow is highest at base of lung, and lowest at apex of lung

Pleura

• Pleura: Double layer membranes surrounding lungs.

Visceral pleura: Layer against lung
Parietal pleura: Layer against thoracic wall and diaphragm
• Pleura cavity: Space between two layers
Pleura fluid: Liquid that fills the pleura cavity, acts as lubricant. Causes layer adhesion.
• Lungs don’t have direct contact with muscle, their ability to be inflated/deflated is mediated
by pleura membrane which links the diaphragm and lungs.

Pulmonary Ventilation: The Mechanics of Breathing

• Air movement occurs via bulk-flow


Movement of molecules due to pressure difference
Air always move from high to low pressure (not partial pressure gradients)
Pressure gradient between mouth and alveoli
• Inspiration: Air enters lungs. 

Diaphragm contracts, and pushes downward, ribs lift outward, raises sternum
Lung volume increases

Intrapulmonary pressure decreases
Air flows into alveoli (high to low pressure/Boyle’s Law)
• Expiration: Air exits lungs.

Diaphragm relaxes, ribs pulled downward
Lung volume decreases

Intrapulmonary pressure increases
Air flow out of alveoli since its pressure is higher than mouth
Pressure Relationships in the Thoracic Cavity

• At nose/mouth, atmospheric pressure. If system opens, then pressure in alveoli equilibrates to

atmosphere (760 mmHg). Respiratory pressures are relative to atmospheric pressure.
• Intrapulmonary pressure: Pressure of alveoli
• Interpulmonary pressure: Pressure of pleura cavity. Slightly lower pressure (-4 mmHg)
Due to vacuum from adhesion (pulling slides apart)

Thoracic Walls: Muscles of Respiration

• Alveoli: Wrapped in elastic bands which create force to collapse them. Additionally, water
lines their walls, and attracts each other to contribute to alveolar collapse.
However, negative pressure (suction) in interpulmonary cavity
• Volume of lung change indirectly by muscle of inspiration
Mediated by interaction of pleura membrane
Modulating elastic recoil of chest wall
• Primary muscles of inspiration: Diaphragm (phrenic), and Intercostals (ventral horn)
• Secondary muscles of inspiration: Larynx, Pharynx, Tongue, Sternocleidomastoid, Trapezius,
Nares.
• Accessory muscles of expiration: Intercostals, Abdominals, Back, and Shoulders

Pulmonary Ventilation: Inspiration

• 1. Inspiration muscles contract (Diaphragm descends; rib cage rises) —> 2. Thoracic cavity
volume increases —> 3. Lungs stretched; intrapulmonary volume increases —> 4.
Intrapulmonary pressure decreases (-1 mmHg) —> 5. Air (gases) flows into lung down pressure
gradient until intrapulmonary pressure = 0 (equal to atmosphere)
• Ribs and sternum elevated and flared as external intercostals contract
Diaphragm moves inferiorly during contraction

Pulmonary Ventilation: Expiration

• 1. Inspiration muscle relax (Diaphragm rises; rib cage descends) —> 2. Thoracic cavity
volume decreases —> 3. Lungs recoil passively; intrapulmonary volume decreases—> 4.
Intrapulmonary pressure increases (+1 mmHg) —> 5. Air (gases) flows out of lung down
pressure gradient until intrapulmonary pressure = 0 (equal to atmosphere)
• Ribs and sternum depressed as external intercostals relax
Diaphragm moves superiorly during relaxation
Boyle’s Law - Experiment and Example

• Experiment: Balloons in sealed chamber, and Y tube open. Increasing volume of chamber
(pulling sheath down) reduces pressure around balloon. Air flows from top of tube into balloon.
This occurs within the body (lung within thoracic cavity)
• Inspiration: Diaphragm pulls down, volume increases and pressure decreases. Air flows in.
• Expiration: Diaphragm raises up, volume decreases and pressure increases. Air flows out.
• General rule —> Volume is inversely proportional to pressure (shrinking size of the jar)
• Example: Atmosphere is 1 ATM. After inspiration, volume is 2900 mL, breathe is 500 mL
V2 = 2900 mL P2 = X mmHg
V1 = 2400 mL P1 = 760 mmHg
P2 = 630 —> ΔP = (P1 - P2) = 130 mmHg

Pressure and Volume in Breathing Cycle

• Transpulmonary pressure: Difference between lung pressures. Tracks effects of Boyle’s Law
Transpulmonary = (Intrapulmonary) - (Intrapleural)
• Volume of breath is inversely proportional to transpulmonary pressure

Impact of Airway Resistance

• Airflow depends on: Pressure difference between two airways and resistance.
Pressure gradient drives air flow, not partial pressure
• Airflow = (P1 - P2) / Resistance
F = ΔP / R
• Airway resistance: Friction that impedes flow of air. Depends on diameter
Chronic obstructive lung disease, asthma and exercise-induced asthma.

Physical factors Influencing Pulmonary Ventilation: Airway resistance

• Bronchioles are the main site of airway resistance

• Resistance increases till Gen-7 (medium-sized bronchi), then decreases (terminal bronchi)

Clinical Application

• Asthma: Results in bronchospasm, and narrowing of airways. Many potential causes

Increased work of breathing, Shortness of breath (dyspnea)
• Exercise-induced asthma: During or following exercise. May impair exercise performance
• Chronic obstructive lung disease (COPD): Increased airway resistance, decreased expiration
Due to constant airway narrowing
Includes two lung diseases:
1. Chronic bronchitis: Excessive mucus blocks airways
2. Emphysema: Airway collapse and increased resistance
• Increased work of breathing leads to shortness of breath
May interfere with exercise and activities of daily living
Pulmonary Ventilation & Alveolar Ventilation

• Volume: The amount of air moved in or out of the lungs per minute
• Tidal volume (VT): Amount of air moved per breath
• Breathing frequency (f): Number of breaths per minute
V = VT * f
• Alveolar ventilation (VA): Volume of air that reaches the respiratory zone
• Dead-space ventilation (VD): Volume of air remaining in conducting airways
V = VA + VD
• Dead space: Anatomical portion of tree that is not participating in gas exchange.
• Rapid, shallow breathing cannot adequately refresh gas in alveoli, buildup of CO2 in arterioles.
Must be overcome for maximum gas exchange
• Pulmonary ventilation refers to the amount of gas moved into and out of the lungs.

Ventilation - Examples

• Example 1: You offer Igor a cup of tea. You measure his tidal volume and respiratory rate and
they are 500 mL and 12 breaths/min. What is Igor’s minute ventilation?
• Minute ventilation = tidal volume * respiratory rate
500 * 12 = 6000 mL/min

• Example 2: Which of the following combinations of respiratory rates and tidal volume would a)
Increases minute volume more? and b) Is more likely to produce a lower PaCO2
Equation 1 = 10 * 1000 mL/breath
Equation 2 = 20 * 400 mL/breath
a) Equation 1
b) Equation 1

Pulmonary Volumes

• Tidal volume (VT): Volume of air inspired/expired during a normal inspiration/expiration

• Inspiratory reserve volume (IRV): Amount of air forcefully after inspiration of normal VT
• Expiratory reserve volume (ERV): Amount of air forcefully after expiration of normal VT
• Residual volume (RV): Volume of air remaining in lungs/airways after most forceful expiration

Pulmonary Capacities

• Inspiratory capacity (IC): IRV + VT

• Vital capacity (VC): IRV + ERV + VT
• Functional residual capacity (FRC): ERV + RV
• Total lung capacity (TLC): IRV + ERV + RV + VT
Minute and Alveolar Ventilation

• Minute ventilation: Total amount of air moved into and out of respiratory system per minute.
Rough estimate of assessing respiratory efficiency.
• Respiratory rate or frequency: Number of breaths taken per minute
• Anatomic dead space: Part of respiratory system where gas exchange does not take place
• Alveolar ventilation rate (AVR): How much air per minute enters the parts of the respiratory
system in which gas exchange takes place. Higher AVR = Higher gas exchange.
AVR = Frequency * TV - density
• Alveolar ventilation rate (AVR) is a better measure than minute ventilation



Effects of Breathing Rate and Depth on Alveolar Ventilation

• As pulmonary parameters change, minute ventilation stays the same. This is why minute
ventilation is a poor evaluation of patients. AVR gives more information.
• Less VT = shallow breathing

Compliance

• Compliance: Measure of the ease which lungs and thorax expand at any given moment.
Essentially the stretchiness the lungs (distensibility)
Greater compliance —> easier for pressure change to cause expansion
Lower compliance —> harder for pressure change to cause expansion
• Certain conditions decrease compliance such as pulmonary fibrosis and edema, and RDS
(respiratory distress syndrome)
• Two components in compliance. 1. Elasticity (elastin surrounding alveoli) and 2. Surface
tension (thin layer of fluid lining alveoli)

Laplace’s Law Applied to Alveoli

• P = (2T)/R
• P = Transpulmonary pressure (mmHg)
• T = Surface tension for particular interface; in alveoli wall (passive elastic tension + surface
tension). Surface tension is reason for water droplets, and same is true for alveoli
• R = Radius of the bubble (distance)
• Alveoli: Similar to balloon covered in thin layer of water.

Laplace’s Law and Surface Tension

• Bubble A, and Bubble B. R and P fluctuate to stablize T. Similar to alveoli

• Bubble A: R = 2 cm, and P = 5 cm H2O
• Bubble B: R = 1 cm, and P = 10 cm H2O
Detergents Reduce Surface Tension

• Detergents are responsible for disrupting surface tension

Surfactant and Surface Tension

• Pulmonary surfactant works to lower surface tension at the alveolar gas-liquid interface.
Made up of phospholipids, principally dipalmitoyl-phosphatidylcholine (DPPC) 

• DPPC reduces surface tension in proportion to its ratio to alveolar surface area
• Surfactant: Endogenous detergent. Amphiphilic. Strongly localize to the air-water interface.
• Water dislikes air-water interface so it dives in bulk solution and away from bubble (air)
• Surface tension decreases bubble size, drives up pressure.
• Water has collapsing effect in alveoli and increases pressure
• Elastic fibers and surface tension help to collapse alveoli
• They assist with exhalation (passive) but not inhalation



DPPC reduces surface tension in proportion to its ratio to alveolar surface area

• Alveoli has dynamic effect since it changes over course of breathing cycle
• End of expiration: Alveoli smallest, water close together, but surfactant is same. Surface area
small. Increased number of surfactant molecule per unit of surface area. Functionally increasing
them means it has lowest surface tension, that facilitates inhalation
• End of inhalation: Alveoli largest, surfactant spaced further apart, less efficient in interrupting
water molecule. Highest surface tension that facilitates exhalation

Compliance

• C = ΔV / ΔP
• Increased Compliance results in increased volume change from the same change in pressure
• Decreased Compliance results in decreased volume change for same change in pressure

Change in Lung Volume from RV

• CL = ΔVL / ΔPTP
• Emphysema: Causes increased compliance in lungs. Same change in pressure, larger
change in volume. Reason is because of loss of elastic tissue. No elastic recoil, exhalation
depends entirely on surface tension but it is inadequate. Exhalation is active process requiring
accessory muscles.
• Fibrosis: Causes decreased compliance. Same change in pressure, smaller change in
volume. Reduction of compliance, lung is stiffer. Requires additional work to bring in normal
volume of air. Needs to generate larger ΔP.
• Normal: 2.5 cm H2O change in pressure
9.2 - Perfusion and Transport

Ventilation-Perfusion Relationships in the Lung

• Pulmonary perfusion circuit: Same rate of flow on right and left similar to cardiac output
Lower pressure system than systemic circulation
• Distribution of blood in pulmonary circuit changes
When standing, majority of blood flow to base due to gravitational force 

During exercise or laying down, more blood flow to apex

Ventilation & Gas Exchange Relationship

• Net effect of ventilation: Exchange air within the alveoli to maintain a partial pressure
gradient which is required for gas exchange in the tissues and in the lungs.
• Blood flow and ventilation rate should be matched to ensure a usable partial pressure
gradient remains despite changing conditions. This is mainly controlled at the local level (lung)
Not regulated by neural or hormonal control, regulated at level of the lung

Ventilation-Perfusion Relationships in the Lung

• Ventilation/perfusion ratio (V/Q): Indicates matching blood flow to ventilation (Ideal = 1.0)
• Apex of lung is under-perfused (< 1.0), and base is over-perfused (> 1.0) (standing-up)
• During exercise —> Light exercise improves V/Q, and Heavy exercise imbalances V/Q

Non-uniformity of Pulmonary Perfusion

• Lung divided into three zones —> Apex, middle, and bottom
Pa = Arteriole pressure, PA = Alveoli pressure, PV = Vein pressure
• Zone 1 (Apex): Under-perfusion. Tends to collapse capillaries. Not much gas-exchange
PA > Pa > PV
• Zone 2 (Middle): Ideal perfusion and ventilation. Best matching.
Pa > PA > PV
• Zone 3 (Bottom): Over-perfusion, poor ventilation.
Pa > PV > PA

VA/Q depends on height in the lung

• Zone 1 (Apex): Ventilation (VA) is highest and perfusion (Q) is lowest (VA/Q > 1)
• Zone 2 (Middle): VA and Q are matched the best. Ideal zone (VA/Q = 1)
• Zone 3 (Bottom): VA is low and Q is highest (VA/Q < 1)
• Blood flow, and ventilation increases from apex to base
• Intersection between blood flow, and ventilation is the ideal point (rib number ~ 3)
Ventilation-Perfusion Ratios

• Apex: Lower lung volume, higher VA/Q, higher PO2, lower PCO2, higher pH, and lower Q.
• Base: Higher lung volume, lower VA/Q, lower PO2, higher PCO2, lower pH, and higher Q.

Ventilation-Perfusion Matching

• Efficient gas exchange between blood and lung requires proper matching of blood flow to
ventilation (ventilation-perfusion relationship)

• Ideal ratio of ventilation to perfusion = 1.0 or slightly greater
Implies a perfect matching on blood flow to ventilation.
• Blood flow regulated by local factors at lung. Redistribution allows maximal gas exchange
• Reduced VA (excessive perfusion - Zone 3) —> Lower PO2 and Higher PCO2 in alveoli —>
Pulmonary arterioles constrict —> Reduced VA and Q
Shunt blood perfusion away from poorly ventilated alveoli to better vented alveoli
• Enhanced VA (inadequate perfusion - Zone 1) —> Higher PO2 and Lower PCO2 in alveoli —
> Pulmonary arterioles dilate —> Enhanced VA and Q

Physical Principles of Gas Exchange

1. Partial pressure: Pressure exerted by each type of gas in a mixture

Dalton’s law explains this
Water vapor pressure plays a role in reducing PO2
2. Diffusion of gases through liquids: Concentration of gas in liquid determined by its partial
pressure and solubility coefficient 

Henry’s law explains this
Equilibrium, partial pressures equal but concentrations aren’t, depends on solubility


Gas Exchange - External Respiration: Overview

• Gas moves across blood-gas interface in the lung due to simple diffusion. 

• The diffusion rate is described by Fick’s law, which states: the volume of gas that moves
across a tissue is proportional to the area for diffusion and the partial pressure difference
across the membrane, and is inversely proportional to membrane thickness.
J = (A * ΔPP) / w
• Gas moves across external and internal interfaces. Alveoli and pulmonary capillaries
(external), and systemic capillaries and interstitial fluid (intracellular)
• Partial pressure gradients (ΔPP) drives diffusion of gases
• In alveoli air: PO2 = 104 mmHg, PCO2 = 40 mmHg
PP gradient determined by deoxygenated blood coming into pulmonary capillary
Gradient acting on O2 is 60 mmHg, favors movement from alveoli into plasma
Gradient on CO2 is reverse
• In pulmonary capillaries: PO2 = 95, PCO2 = 40. Oxygenated blood
• In tissue fluid: PO2 = 40, PCO2 = 46. CO2 higher because of metabolism. O2 is low because
its being consumed.
• Equilibrium establish in 250ms, once blood is 1/3rd through capillary bed it is fully oxygenated.
Large margin of error. Rushing blood 3x faster still allows blood to become oxygenated
Gas Transport: O2 Transport

• 99% of O2 transported is bound to heme group in hemoglobin (Hb)

Oxyhemoglobin: Hb bound to O2

Deoxyhemoglobin: Hb not bound to O2
• Small fraction of oxygen (2%) remains dissolved in plasma

Amount of O2 transported per unit volume of blood is dependent on Hb concentration

• Oxygen transport dependent of plasma Hb concentration

• 1g Hb transports 1.34 mL O2
• Oxygen content of blood (100% Hb saturation) examples:
Males: 150 g Hb/L blood x 1.34 ml O2/g Hb = 200 ml O2/L blood
Females: 130 g Hb/L blood x 1.34 ml O2/g Hb = 174 ml O2/L blood

Gas Transport - Oxygen binding to Hb

• Plasma PO2 is the driving force for Hb and oxygen binding

• Blood without Hb: Oxygen carrying capacity is 3 mL O2/L
• Reduced PO2 with Hb: Oxygen carrying capacity is 100 mL O2/L
• Normal PO2 with Hb: Oxygen carrying capacity is 200 mL O2/L
• Requirement at rest is about 250 mL of O2 per minute, without Hb we could not reach that.

Gas Transport - Hemoglobin

• Hemoglobin is effective because each of the four subunits has a binding site for oxygen
2 𝛼 and 2 𝛽 chains, each subunit has a heme group
• Heme group: Contains a porphyrin ring with an iron atom (Fe2+) in the center
• This Fe2+ reversibly binds O2 in accordance with the law of mass action
Depends on oxygen partial pressure
• Every hemoglobin molecule capable of carrying 4 oxygen
• High affinity state: Oxygen bound very tightly, not readily given up
• Low affinity state: Oxygen bound less tightly, easier to give up.
• Binding of oxygen to hemoglobin is a cooperative process. As one oxygen binds, makes it
easier for subsequent oxygen.

Gas Transport - Oxyhemoglobin Dissociation Curve

• Deoxyhemoglobin + O2 <—> Oxyhemoglobin

• Direction of reaction depends on: Plasma PO2, and Hb/O2 affinity state
• At lung (100 mmHg): High PO2 = Forward reaction (Oxyhemoglobin formation)
• At tissues (40 mmHg): Low PO2 = Reverse reaction (O2 release)
• Oxyhemoglobin Dissociation Curve: PO2 over hemoglobin saturation. Shape is sigmoidal.
• PO2 typically operates between 40-100 mmHg, rarely off the plateau.
PO2 in interstitial fluid = 40 mmHg. PO2 in alveoli air = 100 mmHg
Oxygen-hemoglobin dissociation curve is impacted by pH, temperature, 2-3 DPG

• Four factors impact O2-Hb dissociation curve are pH, Temperature, and 2-3 DPG
1. pH: Decreased pH —> ↓ Hb-O2 affinity. “Rightward” shift of curve. Favors O2 “offloading”
2. Temperature: Increased blood temperature —> ↓ Hb-O2 affinity. “Rightward” shift.
3. PCO2: Increased CO2 partial pressure —> ↓ Hb-O2 affinity. “Rightward” shift.
4. 2-3 DPG: Increased 2-3 DPG —> ↓ HB-O2 affinity. “Rightward” shift. Byproduct of RBC
glycolysis. Increases during altitude exposure. Not major cause of rightward shift in exercise
• “Rightward” shift: Decreases affinity
• “Leftward” shift: Increases affinity
• All come into effect when body is in exercise. Overall affect is to lower Hb-O2 affinity to
delivery O2 to metabolically active tissues
• Normal pH = 7.4. Proportional to Hb-O2 affinity.
• Normal temp = 37C. Inversely proportional to Hb-O2 affinity.
• Normal PCO2 = 40 mmHg. Inversely proportional to Hb-O2 affinity.
• Normal 2,3-DPG = 5 mmol/L. Inversely proportional to Hb-O2 affinity.

The Bohr Effect

• The Bohr Effect: Combination of PCO2 and pH effects

Function is to enhance off-loading of oxygen in metabolically active tissue
• Observation: ↑ PCO2, and ↓ Blood pH causes lower affinity of hemoglobin for oxygen
Rightward shift in the oxygen-hemoglobin dissociation curve
• Mechanism: ↑ PCO2 leads to ↓ blood pH (acidosis) through carbonic anhydrase
↓ Blood pH means ↑H+, it associate with Hb amino acids and reduces Hb-O2 affinity
H2O and CO2 combines to H2CO3 (carbonic acid) which forms HCO3- and H+
• Significance: Enhances O2 delivery proportionally to the metabolic activity of a tissue
↓ metabolic activity → ↓ CO2
More metabolically active —> more oxygen delivered to it

Skeletal muscle experiences lactic acid effect

O2 Transport in Muscle

• Myoglobin (Mb): Protein in skeletal muscle that shuttles O2 from cell membrane, and
sarcolemma and delivers it to mitochondria. Similar to hemoglobin, oxygen-binding protein.
• Myoglobin has a higher affinity for O2 than hemoglobin
Even at low PO2, Mb allowed to bind and store O2 for muscle to O2 reserve

Dissociation Curves for Myoglobin and Hemoglobin

• Myoglobin (Mb): Inverse exponential curve. For PO2 = 20 mmHg —> 100% saturation
• Hemoglobin (Hb): Sigmoidal curve. For PO2 = 20 mmHg —> 50% saturation
Gas Transport: CO2 Transport in Blood

• Smallest fraction of CO2 dissolved in plasma (10%)

• Medium fraction of CO2 bound to Hb (20%) (called carbamino-hemoglobin)

• Largest fraction of CO2 transported as bicarbonate (70%)
• Carbon dioxide transport: CO2 + H2O —> H2CO3 —> H+ + HCO3– (bicarbonate)
First step catalyzed by carbonic anhydrase, but can occur spontaneously
• At tissue: H+ binds to Hb. HCO3- diffuses out, and Cl- diffuses in to RBC
• At lung: O2 binds to Hb (drives off H+), Reaction reverses to release CO2

CO2 Transport in Blood at the Tissue

• CO2 leaves tissue via diffusion —> Dissolves in plasma, or diffuses into cell and combines
with Hb or H2O.
• RBC contains HCO3-—Cl- exchanger where Cl- enters, and HCO3- leaves.

CO2 Transport in Blood at the Lung

• Dissolved CO2 enters alveoli via diffusion

• CO2-Hb gives up CO2, and then diffuses out of RBC and into alveoli
• HCO3-—Cl- exchange reversed. HCO3 enters, and Cl leaves. HCO3 binds to H+ in RBC to
make H2O and CO2 which diffuses out of cell and into alveoli according to PP gradients.

Summary: Gas Transport

• Over 99% of the O2 transported in blood is chemically bonded with hemoglobin. The effect of
PO2 on the combination of Hb-O2 is illustrated by the S-shaped O2-hemoglobin dissociation
curve. We exist at plateau of curve so Hb almost 100% saturated

• An increased temperature and decreased blood pH results in a rightward shift in the O2-
hemoglobin dissociation curve and a reduced affinity of Hb-O2

Hypoxia

• Hypoxia: Occurs when alveolar PO2 decreases

• Solubility rules indicate that if PO2 decreases, then the amount dissolved in blood also drops
(hypoxic condition)

• Factors that cause low arterial PO2
1. Not enough O2 reaching alveoli (Unable to refresh gradient)

2. Exchange between alveoli and pulmonary capillaries has a problem 

3. Not enough O2 transported in blood
9.3 - Regulation of Ventilation

Overview

• Respiratory system maintains PaCO2, and PaO2 within narrow range

• Respiration contributes to acid/base balance since PCO2, and PO2 influence blood pH
• Respiratory maintenance of arterial PCO2, PO2, and blood pH controlled unconsciously via
negative feedback system which changes respiration and return variables to normal.

Quiet Breathing

• Breathing: Cyclic excitation of respiratory muscles of inspiration by motor neurons

• Inspiration: Respiratory rhythm generator activates inspiratory spinal motor neurons
Causes muscles (diaphragm and external intercostal) on inspiration to contract
• Expiration: Passive. Occurs when the action potentials within neurons cease, muscles relax
Elastic recoil of lungs, and surface tension within alveoli

Regulating Ventilation

• Ventilation controlled in the brain stem by a neural network

• Ventilatory control must
1. Establish cyclic automatic rhythm for contracting the muscles of inspiration
2. Adjust the rhythm to meet changing metabolic and non-metabolic needs

Quiet Breathing

• Central pattern generator (CPG): Specific site in brain stem containing neural circuits that
control rhythmic behaviors. Establishes complex motor programs in absence of sensory
feedback, but it utilize senses to adjust output of CPG.

• Inspiration increases in AP in spinal motor neurons innervating the muscles of inspiration
Expiration occurs when the action potentials cease, these muscles relax
• CPG is modulated by respiratory gas levels, pH, emotions, and voluntary efforts

Basic Respiratory Control Feedback Loop

• Chemoreceptors —> Brainstem Respiratory Centers (CPG) —> Modulate breathing

muscles —> Change Alveolar Ventilation Rate (AVR) —> Change Blood pH, PaO2, PaCO2
• Respiration controlled via negative feedback circuit. Involves afferent stimuli sent into
integrative hub which analyzes and coordinates efferent response. Yields stable values.
• Lung receptors include stretch-, irritant-, and J-receptors which send afferent stimuli
Only activated in special circumstances, do not contribute to normal control
Ventilation and Acid-Base Balance

• Increased ventilation causes CO2 exhalation which reduces blood PCO2, and H+ via
bicarbonate reaction. This effectively increases blood pH.
<——————————————————————————— Lung
CO2 + H2O <—Carbonic anhydrase—> H2CO3 <—> H+ + HCO3-
Muscle ——————————————————————————>
• Bicarbonate reaction is reversible and driven by mass-action
• Increased ventilation results in decreased CO2
Reduces PCO2 and H+ concentration (pH increase)
• Decreased ventilation results in increased CO2
Increases PCO2 and H+ concentration (pH decrease)

Central Chemoreceptors

• Central Chemoreceptors: Anatomical neuronal chemoreceptors below the ventral surface of

the medulla, and close to brainstem respiratory centers
• Feedback source for assessing ventilation effectiveness. Provides major drive for breathing.
• Senses arterial CO2 indirectly, and CSF pH directly
• Sensor of negative feedback loop controlling respiration to maintain constant arterial CO2
• Send signals to brain stem respiratory centers, and targets inspiratory center.
• When CSF pH is decreased due to ↑ PCO2, increased stimuli activates respiratory center to
Increasing respiratory drive, enhancing alveolar ventilation and elimination of CO2
• When CSF pH is increased due ↓ PCO2, decreased stimuli which lowers basal stimulation.
Reducing respiratory drive, alveolar ventilation and elimination of CO2
• CO2 crosses blood brain barrier into CSF and forms bicarbonate + H+, decreasing pH

Effect of Central Chemoreceptors on Ventilation and pH

• Central chemoreceptors monitor CO2 and determine ventilation and pH

• Ventilation: Proportional to inspired PCO2. Enhanced PCO2 causes increase in total
ventilation until plateau, and drops back down when inspired PCO2 returns to zero.
• Blood pH: Inversely proportional to ventilation. As it decreases then ventilation increases.
• CSF pH: Proportional to blood pH. For both respiratory (steep) and metabolic (shallow)
acid-base changes, as blood pH decreases then CSF pH decreases.

Peripheral Chemoreceptors

• Peripheral Chemoreceptors: Neural chemoreceptors in carotid bodies and aortic arch. Send
afferents to brainstem respiratory centers (inspiratory center) and modulate respiratory drive.
Carotid body: Located at bifurcation of each common carotids
Aortic body: Scattered along underside of aortic arch
• Not the same structures as baroreceptors (mechanical stretch)
• These are sensitive to ↓ PaO2. Also ↑ PaCO2 and ↓ blood pH, but to a much lesser extent.
• Important sensory of negative feedback loop controlling respiration, arterial O2 and pH 

• Critical for responding to hypoxemia (PaO2 < 80 mm Hg)
Experiment

• Experiment: Vm measured for isolated a chemoreceptor from the carotid body 


• ↓ PaO2 is primary stimulus for peripheral chemoreceptors
• Anoxia is characteristic of ↓ PaO2, this causes Vm depolarization
• ↓ PO2 results in increased AP discharge/sec.
If ↑ PCO2 and ↓ pH, then sensitivity increased
For the same reduction in PO2, there is greater discharge rate and vice versa.

• The carotid body is sensitive to: Hypoxia, and both components of respiratory acidosis (High
pCO2 (hypercapnia), Low pH (acidosis))

Pulmonary Stretch Receptors

• Pulmonary stretch receptors are mechanoreceptor found in bronchial smooth muscle 


• Detect physical stretch of the airway 

• Activation (stretching) results in increased afferent output which decreases respiratory rate 

Increases expiration length
• Known to have an effect in animals but significance in humans is equivocal 




Irritant Receptors

• Irritant receptors are sensory receptor found in respiratory tree epithelium


• Detect variety of chemical irritants
• Activation results in: Coughing, sneezing, and bronchoconstriction

J Receptors

• Sensory receptors deep in respiratory tree. Located in alveolar septa “juxtaposed” to

pulmonary capillaries.
• Type of pain (nociceptor) receptor coupled to unmyelinated C-fibers carrying pain information

• Activated by blood engorgement of pulmonary capillaries 

Indicative of left heart dysfunction 

Increases in pulmonary interstitial fluid volume (pulmonary edema) 

• Activation causes reflexive increase in ventilation rate 

• Plays a role in dyspnea seen in patients with congestive heart failure and pulmonary edema 

• Dyspnea is a sensory experience where it feels like they have difficulty breathing
• Not activated normal physiology, but part of pathophysiology of CHF and edema.
Respiratory Control Center

• Stimulus for inspiration comes from four respiratory rhythm centers

In Medulla: pre-Bötzinger Complex and retrotrapezoidal nucleus
In Pons: Pneumotaxic center and caudal pons
• Group pacemaker hypothesis suggests that regulation of breathing is under redundant control

Input to the Respiratory Control Center to increase ventilation

• CO2, O2, and pH levels influence ventilation

CO2 has biggest influence. O2 and pH are influencing factors
• Ventilation regulation comes from neural or humoral input
• Humoral chemoreceptors
Central chemoreceptors

Located in the medulla

Sensitive to ↑ PCO2 and ↑ H+ concentration in CSF
Peripheral chemoreceptors
Aortic and carotid bodies (most important)

Sensitive to ↑ PCO2, H+, and ↓ PO2, K+ in blood
Lung CO2 receptors
Sensitive to ↑ PCO2
• Neural input: From higher brain centers (motor cortex) and skeletal muscle
mechanoreceptors

Control of Ventilation at Rest

• Inspiration and expiration produced by contraction and relaxation of diaphragm

• Controlled by somatic motor neurons in the spinal cord that innervate these skeletal muscles
Controlled by respiratory control centers in medulla oblongata

Physiological Algorithm of Respiratory Control

• ↑ PaCO2 —> Central chemoreceptors —> Brainstem respiratory centers —> ↑ Muscles of
respiration —> ↑Alveolar Ventilation —> Elimination of alveolar CO2 —> ↓ PaCO2
• ↓ PaO2 + ↓ Blood pH —> Peripheral chemoreceptors —> Brainstem respiratory centers —>
↑ Muscles of respiration —> ↑ Alveolar Ventilation —> ↑ PaO2 + ↑ Blood pH
• Respiratory pattern determines AVR which determines PaO2 and PaCO2 which adjusts
blood pH. These values allow negative feedback circuit that stabilizes them.
• Increased PaO2 reduce afferent stimuli from peripheral, this does little to suppress respiration.
• Changes in PaCO2 are sensed by both central and peripheral, but central has larger role in
coordinating respiratory changes
• Acidosis increases respiratory drive, alkalosis decreases respiratory drive
• pH is sensed by both central and peripheral (aortic bodies) receptors. Peripheral are
dominant in pH changes.
Neurons that Control Ventilation

• Respiratory Pattern Generator (RPG) exhibits motor behaviors associated with inspiration
such as nostril flaring, tongue, larynx, pharynx changes that keep airways open.
• Location of central respiratory pattern generation is within medulla. Two generators on
either side of the midline. Neural circuits necessary for normal ventilation via respiratory rhythm
• Phrenic and intercostal motor neurons responsible for breathing, not RPG.
• Other sites like the Pons shape respiratory output
• Brain sends commands to diaphragm via upper spinal cord

Respiratory Control Centers in the Brainstem

• Brain stem refers to both Pons and Medulla

• Pons: Contains Pneumotaxic center, and Apneustic center
• Medulla: Medullary respiratory center contains dorsal, and ventral respiratory groups

Respiratory Control Center: Medulla

• Dorsal Respiratory Group (DRG)

Consists mostly of inspiratory neurons (interneurons, premotor neurons)
Controls basic rhythm
Innervate the motor neurons of the diaphragm and external intercostal muscles
Innervate VRG

Receive sensory information from vagus and glossopharyngeal nerves
Integrate all sensory information coming into respiratory system
• Nucleus of the Solitary Tract (NTS) 

Peripheral chemoreceptors
Receptors in the lungs

Stimulates the diaphragm 

• Ventral Respiratory Group (VRG)
Contains both Inspiratory and expiratory neurons
Like DRG contains interneurons, premotor neurons

Active in exercise and stress

Innervates larynx, pharynx , thorax, abdomen, diaphragm and intercostals
Lays ventral to DRG and forms column extending from pons to spinal cord
• DRG and VRG are coupled. DRG reside around NTS
DRG plays sensory role, and VRG plays efferent role
Ventral Respiratory Group


• Three distinct parts of the VRG 

1. Rostral portion: Bözinger complex. Contains interneurons that drive expiratory activity of the
caudal divisions of VRG.
Nucleus retrofacialis 

2. Intermediate portion: Pre-Bözinger complex. Contains neurons leave medulla through CN IX
and X. These somatic motor neurons that innervate the pharynx, larynx which maximizes
diameter of upper pathways during inspiration. Also contains premotor neurons that project to
inspiratory motor neurons in spinal cord and medulla. Role is Inspiratory. 

Nucleus ambiguus and nucleus paraambiguus 

3. Caudal portion: Contains premotor neurons which innervate accessory muscles of
expiration (internal intercostals, abdominals). Role is Expiratory.

Nucleus retroambiguus 


Respiratory Control Center: Pons

• Pons modulates pattern generator (respiratory input), but does not initiate it. Two parts
1. Apneustic Center: Caudal pons. Stimulates inspiratory neurons of DRG and VRG

Responsible for apneustic breathing (long gasping inspiration, brief expirations)
2. Pneumotaxic Center: Includes parabrachial nucleus and Kölliker-Fuse nucleus of the rostral
pons. Both inhibits the inspiratory center of medulla. Controls the inspiratory “off-switch”, i.e.
determines length of inspiration. 

Increased stimulation of pneumotaxic center increases respiratory rate

Inhibition of pneumotaxic center prolongs inspiratory time

Regulation of Ventilation - Brain Stem

• Normal breathing generated by interaction of respiratory rhythm centers in medulla and pons.
Control Model:
1. At rest, rhythmic ventilation is due to spontaneously discharging neurons
Pre-Bötzinger complex (pacemaker)
2. Respiratory neurons (DRG & VRG) in medulla control inspiratory & expiratory muscles 

3. Neurons in the Pons (PRG), and DRG integrate sensory input and influence activity of the
medullary neurons (central pattern generator)

4. Ventilation under continuous modulation by reflexes, sensory input and higher brain
Modified output for speech, singing, and emotional expression
Neural activity during respiratory cycle

• Two phases of eupneic breathing (normal respiratory pattern at rest, i.e. eupnea)
• 1. Inspiration: Increase in lung volume (TV), increase inspiratory airflow, increase phrenic
nerve activity to diaphragm. Vm increases in inspiratory-ramp neurons, and decreases in
early-expiratory neurons.
• 2. Expiration: Decrease in lung volume (TV), increase expiratory airflow, no phrenic nerve
activity. Vm decreases in inspiratory-ramp neurons, and increases in early-expiratory
neurons during first half then repolarization.
• AP driving muscles of inspiration occurs gradually over 2 seconds, instead of burst
Prevents gasping behavior and allows for slow, steady increase in lung volume.

Inspiratory Ramp Signal

• Rise of ramp signal modulated during heavy respiration (exercise), allows lungs to fill quicker
• Limiting point is when ramp signal stops. Method of regulating rate of respiration
• Reaching limiting point faster, signal stops faster, switches to expiration. More rapid ventilation

Effect of Arterial PCO2 on Ventilation

• PaCO2 is directly proportional to ventilation

As PaCO2 increases, then linear increase in ventilation rate

Effect of Arterial PO2 on Ventilation

• PaO2 is inversely proportional to ventilation

As PaO2 increases, then ventilation decreases
• Hypoxic threshold: PaO2 = 70 mmHg
Further reduction dramatically elevates ventilation
Once PaO2 = 60, hypoxemia is established which causes hyperventilation

Effect of PaO2 on ventilation at different PaCO2 values

• As PaCO2 increases, peripheral chemoreceptor sensitivity increases. This causes a

ventilation rate is much higher than if PaCO2 was lower.
• Elevated PaCO2 elevates ventilation rates before ticking off hypoxemia threshold (60)
• Important in reestablishing normal PaO2

Transition from Rest to Exercise

• PO2 slightly decreases, then quickly stabilizes

• PCO2 slightly increases, then quickly stabilizes
• Ventilation (VE) increases until reaching steady state
• PO2, and PCO2 consistency due to increased ventilation rate and alveolar ventilation
Ventilatory Control During Exercise

1. Sub-maximal exercise
Primary drive by higher brain centers (central command). Decision to exercise.
Fine tuned by humoral (both) chemoreceptors, and neural feedback from muscle
2. Heavy exercise: linear rise in VE
Blood acidification and lactic acid stimulates carotid bodies
Also K+, body temperature, and blood catecholamines may contribute

A Summary of Respiratory Control During Sub-maximal Exercise

• Primary drive to increase ventilation during exercise comes from Higher brain centers —>
Respiratory control center (Medulla oblongata) —> Respiratory muscles —> ↑ Ventilation
• Skeletal muscles (chemoreceptors, mechanoreceptors) and peripheral chemoreceptors
influence respiratory control centers
• Purpose is to maintain normal PaCO2, PaO2, and arterial blood pH

Regulation of Ventilation - Higher Brain Center Influence

• Higher brain function NOT required for normal ventilation, or regulation of respiratory cycles
Central pattern generators in Medulla, some modulation from the Pons
• Conscious (holding breath) and unconscious higher brain function influences ventilation
Emotional state: Fear/anxiety/excitement = increased respiratory cycle rate

Hyperventilation and Diving

• Hyperventilation before breath holding... good or bad?

It allows divers to hold their breath for longer, but it is dangerous
• Hyperventilation causes the same PaO2, but lower PaCO2, and higher pH
• During normal breath hold, O2 decreases. Person feels need to breath due to increased
PaCO2 and acidosis. Stimulates respiratory center and increases desire to take breath.
Possible to hold breath for over 5 minutes with hyperventilation and 100% oxygen
• With practice, body can resist stimuli for longer. CO2 accumulation still causes release of
breath hold. This occurs prior to loss of sufficient PO2 so we remain conscious
Hypoxic stimulus triggers respiration before CSF pH falls enough to do so
• Due to hyperventilation, diver feels need to breath from decreased PaO2 stimulating carotid
chemoreceptors
• Pressure increases 4x during the dive (compresses TLC of 6L to 1.5L)
PaO2, PaN increase, but PaCO2 doesn’t. Little in lungs, body has buffering capacity
• As the diver ascends, pressure decreases 4x. This causes 4x reduction in PaO2. Rapidly
falling cerebral O2 causes them to pass out during ascent.
• Danger of hyperventilation applies to all breath-holding divers. Reduction in PaO2 when
coming to surface causes unconsciousness from even shallow pools (2m)
Learning objectives (Unit 9):

1. Explain four processes collectively referred to as respiration: a. Pulmonary ventilation,

b. External respiration, c. Transport of respiratory gases, d. Internal respiration

1. Pulmonary Ventilation: Breathing air in and out. Refreshes gases. Convection.

2. External respiration: Gas exchange between alveoli and pulmonary capillaries. Diffusion.

3. Perfusion/Transport: Oxygenated blood from lungs to systemic circulation.Convection.

4. Internal respiration: Gas exchange between systemic capillaries and cells. Diffusion.

2. Understand how convection and diffusion work together to maximize gas exchange

Large organisms can not rely solely on diffusion for metabolic needs. Convection allows bulk
movement of gas or liquid. Occurs in lung airways and systemic circulation. External and
internal convection systems.

3. Describe the changes that occur in each of the following parameters with each
generation number of the tracheobronchial tree: a. Diameter of the conducting
passageways b. Support structures (Cartilaginous support, Elastic fibers) c. Epithelium
(Cilia, Mucous secreting cells), d. Smooth muscle

1. Length of airways: Diameter decreases but aggregate x-sectional area increases

2. Support structures: Cartilage rings present 1-10. Elastic fiber replaces cartilage from 11-23.

3. Epithelium: Upper has many cilia and little mucous secreting cells. Lower has less of both.

4. Smooth muscle: Replace cartilage from 11-23. Wrapped around bronchioles but not alveoli.

4. Distinguish the conductive zone and respiratory zone of the tracheobronchial tree

Conductive zone: Site of convection. Conducts air to respiratory zone. Humidifies, warms, and
filters air. Components are trachea, bronchus, bronchi, and bronchioles. (1-16)

Respiratory zone: Gas exchange between air and blood. Components are respiratory
bronchioles, alveolar ducts, alveolar sacs, alveoli and surfactant. (17-23)

5. Describe the following: alveolar duct, alveolar sac, and alveolus.

Alveolar duct: Connect bronchioles to alveolar sacs

Alveolar sac: Branches off alveolar duct, and contains many alveoli.

Alveolus: Single epithelial layer. Type 1 pneumocytes are thin and used in diffusion (gas
exchange). Type 2 pneumocytes are thicker, produce surfactant, and proliferate when
damaged. Water lines inside and surfactant lines outside. Covered in elastic bands.

6. Identify two circulatory systems of the lungs, and key differences between them

Pulmonary circulation: Deoxygenated blood to alveoli. High volume. Low pressure. Contains
high angiotensin converting enzyme. Affected by gravity.

Bronchial circulation: Oxygenated blood to lung tissues (except alveoli). Low volume. High
pressure. Not affected by gravity.

7. Describe the relationship of the visceral and parietal pleura

Visceral pleura: Layer against lung

Parietal pleura: Layer against thoracic wall and diaphragm

Lungs do not have direct contact with muscle. Inflation/deflation is mediated by pleura
membrane linking the diaphragm and lungs. Contains pleura fluid acting as lubricant.

8. Identify: Intrapulmonary pressure, Intrapleural pressure, and Transpulmonary pressure

Intrapulmonary pressure: Pressure of alveoli

Intrapleural pressure: Pressure of pleura cavity. Slightly lower pressure (-4 mmHg)

Transpulmonary pressure: Difference between pressures. (Intrapulmonary) - (Intrapleural)

9. Identify the muscles of inspiration and expiration. Relate their function to Boyle’s Law

Inspiration: Diaphragm, and external intercostals (Primary). Larynx, pharynx, tongue,

sternocleidomastoid, trapezius, and nares (Secondary).

Expiration: Internal intercostals, abdominals, back, neck, shoulders (Secondary).

Boyle’s Law: V1P1 = V2P2. Diaphragm rises, external intercostals contract which raises ribs
and increases volume which decreases pressure. Diaphragm rises, external internal
intercostals relax which lower ribs and decreases volume which increases pressure.

10. Demonstrate a quantitative understanding of the Gas laws relevant to the unit on
Respiratory Physiology (Fick’s, Dalton, Henry’s, etc.)

Fick’s Law: Vgas = A/T * D * (P1 - P2)

Dalton’s Law: Pair = PO2 + PCO2 + PN2
Henry’s Law: [O2]Dis = S * PO2
Boyle’s Law: P1V1 = P2V2
11. Describe regional differences in perfusion of the lungs and explain the effect on
ventilation-perfusion

Distribution of blood is different when standing and laying down due to gravity. When standing,
majority of blood in base (High VA and Low Q), and least amount in apex (High VA and Low Q)

Zone 1 (Apex): PA > Pa > PV (VA/Q > 1)

Zone 2 (Middle): Pa > PA > PV (VA/Q = 1)

Zone 3 (Bottom): Pa > PV > PA (VA/Q < 1)

12. Explain ventilation-perfusion matching

Blood flow should be matched to ventilation to ensure efficient gas exchange. Defined by ratio
of alveolar ventilation (VA) divided by perfusion (Q) = VA/Q. The ideal ratio is 1.0. Apex > 1.0,
and base < 1.0.

13. Explain how lung compliance is affected in different disease conditions

Pulmonary compliance is increased by emphysema, and decreased by pulmonary fibrosis,

pulmonary edema, and respiratory distress syndrome. Emphysema causes loss of elastin,
exhalation becomes active process. Fibrosis becomes stiffs, requires more work to fill lungs.

14. Use Laplace’s Law to describe how the distending pressure of a bubble is influenced
by surface tension and the size of the bubble. Explain how surfactant and the principle of
interdependence affects alveolar function

Laplace’s Law: The larger the vessel radius, the larger the wall tension (surface tension)
required to withstand a given internal fluid pressure or P = (2T)/R or T = (P*R)/2. P and R
fluctuate to stabilize T.

Surfactant (DPPC): Lowers surface tension in proportion to its ratio to alveolar surface area by
attaching to water via hydrophilic segment while hydrophobic part sticks out. End of inhalation
has highest surface tension which facilitates exhalation.

Alveolar interdependence: If alveolus in center begins to collapse then wall stress increases in
adjacent alveoli which then holds the collapsing one open.

15. Explain the physical principles and laws that govern gas exchange

1. Partial pressure: Pressure exerted by each type of gas in a mixture. Dalton’s law.

2. Diffusion of gases through liquids: Concentration of gas in liquid determined by its partial
pressure and solubility coefficient. Henry’s law explains. At equilibrium, partial pressures equal
but concentrations aren’t.

16. Discuss hemoglobin-oxygen binding, and the factors that affect it

Hemoglobin: Binds with oxygen to transport it (98%), also transports CO2 (20%)

pH: Proportional to Hb-O2 affinity. Decrease causes rightward shift (Bohr)

PCO2: Inversely proportional to Hb-O2 affinity. Increases causes rightward shift (Bohr)

Temperature: Inversely proportional to Hb-O2 affinity. Increases causes rightward shift

2-3 DPG: Inversely proportional to Hb-O2 affinity. Increases causes rightward shift

17. Describe how ventilation is regulated by the central nervous system.

Ventilation initiated by inspiratory motor neurons controlling diaphragm, and intercostals which
are activated by the respiratory rhythm generator (pre-Botzinger pacemaker). Ventilation
proportional to inspired PCO2.

Negative feedback: Chemoreceptors —> CPG —> Muscles —> AVR —> Variable changes

Ventilation controlled by neural and humoral inputs sent to RPG. Humoral input is central,
peripheral chemoreceptors, and lung CO2 receptors. Neural input is higher brain centers and
skeletal muscle mechanoreceptors.

Ventilation control located in brainstem. Pons contains pneumotaxic (rostral), and apneustic
(caudal). Pneumotaxic responsible for off-switch, and apneustic for stimulating DRG, VRG.
Medulla contains nucleus of the solitary tract, dorsal, and ventral respiratory groups.

NTS: Peripheral chemoreceptors, lung receptors. Stimulate diaphragm.

Doral Respiratory Group: Mostly inspiratory neurons. Controls basic rhythm. Innervate
diaphragm, external intercostals, and VRG. Receives and integrates senses. Afferent.

Ventral Respiratory Group: Both inspiratory and expiratory neurons. Innervates larynx, pharynx,
thorax, diaphragm, and external intercostals. Sends signals. Efferent.

Rostral portion: Bozinger, n. retrofacialis. Drive expiratory in caudal

Intermediate: Pre-Bozinger, n. ambiguus, n. paraambiguus. Inspiratory role.

Caudal portion: N. retroambiguus. Expiratory role.

18. Central pattern generator: a. Modulated by pO2, pCO2, pH, emotions, voluntary
efforts, b. The brainstem areas that regulate ventilation, c. Non-neural regulation of
respiration

Central pattern generation: NTS, VRG, and DRG. Controls rhythmic behavior. Does not require
senses but utilizes them. Modulated by reflexes, higher brain centers, pons, gas levels, pH,
emotions, and voluntary efforts (speech, singing). PaCO2 proportional, and PaO2 inversely
proportional to ventilation. As PaCO2 increases, peripheral sensitivity increases.

Neural regulation: Central chemoreceptors senses CSF pH directly, and PCO2 indirectly. They
increase respiratory drive when CSF pH decreases. Higher brain centers and skeletal muscle
mechanoreceptors.

Non-neural regulation: Lung receptors including CO2, stretch, irritant, and J receptors.
Peripheral chemoreceptors in carotids bodies and aortic arch. Directly sensitive to decreased
PaO2, and pH, increased PaCO2.

 Unit 10 - Gastrointestinal System

10.1 - Structure and Motility

Overview

• Six main functions of the GI system which are all tightly regulated by ANS and endocrine
1. Food movement through the alimentary tract
2. Secretion of digestive juices

3. Digestion of the food

4. Absorption of water, electrolytes, vitamins, and nutrients

5. Circulation of blood through the GI organs to carry away the absorbed nutrients

6. Control (regulation) of all these functions

Stages in Food Processing

• Four stages of food digestion

1. Ingestion: Taking food in, eating. Oral cavity.
2. Digestion: Two types. Liberates absorbable nutrients. Stomach
2a. Mechanical: Food is ground down and cut, dissembled into smaller parts
2b. Chemical: Enzymatic hydrolysis of food, splits bonds.
3. Absorption: Nutrients enter body cells. Small intestine.
4. Elimination: Anything that remains behind in GI tract, undigestible material. Rectum

Digestive System Components

• Alimentary canal: Mouth —> Esophagus —> Stomach —> Small intestine —> Large intestine
—> Rectum —> Anus
Accessory structures (salivary glands, pancreas, liver, gall bladder) connected by ducts
• Each part is specialized for its unique function, reflected in structure
Mouth in mechanical digestion, teeth grind food
Esophagus in transport. Specialized muscular tube, no digestion, or absorption.
Stomach in size to accommodate large volumes of food
Digestive Sphincters

• Seven sphincters regulate movement of food through alimentary canal

• Anatomical sphincters: Rings of visible smooth muscle that contract and relax. Separate
tissue participates in shutting off passage.
• Physiological sphincter: Rings of invisible smooth muscles that prevent reflux. Muscle is
simply thicker, not separate part of the organ. Imperfect, and sometimes reflux.
1. Upper esophageal sphincter: Closest to oral cavity
2. Lower esophageal sphincter: Not anatomical, but instead a physiological sphincter.
3. Pyloric sphincter: Located before duodenum
4. Oddi sphincter: Regulates passage of secretions into duodenum
5. Ileocecal valve: Regulates passage from small intestine to large intestine
6. Internal anal sphincter: Ring of smooth muscle
7. External anal sphincter: Ring of skeletal muscle

Structure of the GI wall

• Lumen —> Mucosal epithelium —> Lamina propria —> Muscularis mucosae —> Submucosa
—> Submucosal nerve plexus —> Muscularis externa —> Myenteric plexus —> Serosa surface
• Mucosal surface: Inner-most surface facing lumen. Epithelial layer specialized for secretion
and absorption.
• Lamina propria: Connective tissue, vasculature, and mucosa-associated lymphoids which
screen for pathogenic substances.
• Submucosa: Connective tissue. Contains bodies for glands, and lots of vasculature.
• Submucosal nerve plexus: In-between submucosa and circular muscle. Dense layer matrix.
• Muscularis externa: Inner circular smooth muscle layer, and outer longitudinal smooth
muscle. Contraction changes shape/surface area.
• Myenteric plexus: Between longitudinal smooth muscle and circular smooth muscle.
• Serosal surface: Outer-most surface facing interstitial fluid. Thin layer of connective tissue
and epithelial cells.
• This is the structure of entire alimentary canal except one exception (stomach)

Extrinsic Innervation

• Alimentary canal is innervated by both extrinsic and intrinsic component

Extrinsic: Autonomic nervous system (ANS)
Intrinsic: Enteric nervous system (ENS) which is influenced by ANS
• Parasympathetics supplied by vagus nerve (to ascending colon), and pelvic nerves (the rest)
Pre-ganglionic are long, post-ganglion located in wall of GI tract
Post-ganglionic release ACh and neuropeptides (Substance P, VIP)
• Sympathetic
Pre-ganglionic are short, and synapse on sympathetic ganglia
Post-ganglionic release NE
Enteric Nervous System (ENS)

• ENS encompasses three types of reflexes

1. Short length: Reflexes that are integrated entirely within the gut wall enteric nervous system
Controls secretion, mixing, local effects
2. Medium length: Reflexes from the gut wall to the prevertebral sympathetic ganglia that
then project back to the GI tract. Leave alimentary canal, but not conscious.
Links two segments of GI tract (i.e. enterogastric reflex)
Sensory information between to organs to coordinate function
3. Longer length: Reflexes from the gut to the spinal cord or brain stem and back to the gut
Important in controlling motor and secretion functions.
General inhibitory effect on GI tract (main pain reflexes)

Motility

• Motility: Contraction, and relaxation of walls of alimentary canal and sphincters

• Mixing: Grinding, mixing, and fragmentation (Segmentation)
Grinding important because it increases surface area available for enzymes
Mixing important because mixing food with secretions
• Peristalsis: Propulsion. Also spreads contents out along surface along epithelium.
• Phasic contractions: Periodic contractions followed by periodic relaxation. Found in
alimentary canal, each one has unique frequency for contractions. Peristalsis and mixing.
• Tonic contractions: Smooth muscle maintains constant level of tension (tone), no regular
periods of relaxation. Applies to sphincters. Tone maintained to regulated propulsion.

Hormonal Control - Motility

• Hormones responsible for motility: Motilin, CCK, Secretin, GIP

All released into circulation, must be carried to target which expresses receptor
Most hormones impact secretion. These impact secretion but perform an additional duty
• Motilin: Stimulates gastric, and intestinal motility. Stimulated by Fat, Acid, and Nerves.
Used during fasting. Induces contractions (Hunger pains)
Secreted by M cells
• CCK: Inhibits gastric emptying. (Cholecystokinin)
• Secretin: Inhibits gastric emptying.
• GIP: Inhibits gastric emptying. (Gastrointestinal inhibitory peptide)
• All secreted in small intestine (duodenum, jejunum) and stimulated by protein, fats, and
acids (except motilin)
Propulsive Movements - Peristalsis

• Propulsive movement (peristalsis) is uniform, occurs at any point along length of GI smooth
• Behind distension is ring of contraction called peristaltic contraction.
• Leading wave of relaxation followed by ring of contraction that sweeps along, and pushes
contents of lumen along the GI tract. Requires functioning myenteric plexus.
Some genetic conditions disrupt myenteric plexus, and peristalsis is limited.
• Parasympathetic stimulate contractions, and sympathetics stimulate relaxation
Blocking ACh inhibits peristalsis. Trigged by opiates
• Stimuli: Distension of wall (pushing GI walls apart), food to be digestion, irritation of wall
(spicy/toxic food), increased parasympathetic tone.
• Every segment of alimentary canal has unique contraction frequency (X contractions / min)
Parasympathetics does not increase contraction frequency, but it increases strength

Chewing and Saliva

• Breaking down food, and mixing it with saliva (lubricant) facilitates swallowing
Carbohydrate and fat digestion begins in mouth (amylase, lipase) gives a good taste
• Saliva: Contains mostly water, electrolytes (Na, K, Cl, PO4, HCO3), enzymes, mucin, IgA
• Lysozyme: Bacterial that prevents bacterial growth
• IgA: Antibodies that protect against microorganisms
• Defensins: Local antibiotic, and cytokine. Attracts immune cells
• Mucin: Made up of glycoproteins, makes saliva sticky

Types of Motility: Three Phases of Swallowing

1. Oral phase: Mostly voluntary. Epiglottis raised, UES contracted, patent airway.
Tongue manipulates food forming bolus which moves towards back of throat (voluntary)
Once food in back of throat, sensory information carried to CNS triggers swallowing
2. Pharyngeal phase: Food enters pharynx, epiglottis drops down, UES relaxes. Propels food
into the esophagus. UES releases which causes wave of distension and wave of contraction
3. Esophageal phase: UES contracts, and epiglottis rises. Food into stomach.
• Primary peristaltic wave: Food enters esophagus, peristalsis sweeps into stomach, LES relax
• Secondary peristaltic wave: Any remaining food in esophagus causes distension and triggers
another wave.
• As wave reaches stomach, the stomach becomes prolapsed, accommodates food (receptive
relaxation)
• Physiological sphincter relaxes as food enters esophagus
Gastric Motility

• Three divisions of stomach

• Fundus: Upper-most portion (5%)
• Body: Middle portion (70%)
• Antrum: Bottom-most portion (25%)
• Lesser and greater curvature of stomach
• Orad region: Thinner muscles. Location of receptive relaxation (30%)
• Caudad region: Thicker wall of muscles. Propels food into small intestine (70%)

Stomach - Structure of the GI Wall

• Stomach is an exception to structure of the rest of the GI tract

• Stomach has additional third, innermost layer of smooth muscle called oblique layer which
are perpendicular to others. Important mixing within stomach. Three motions in stomach.
• Receptive relaxation: Allow accommodation of food mediated by vagovagal reflex. Triggered
by stomach wall stretch. Causes relaxation of smooth muscle in stomach. NT used are VIP.
• Segmentation: Reduce size of food and mix it
• Peristalsis: Propulsive movements
• Rate of delivery of gastric contents to small intestine is tightly regulated, provides adequate
digestion time and prevents overwhelming of chyme.

Mixing

• Mixing waves take place in caudad region

• Stomach has 3-5 electrical waves per minute, frequency doesnt change, but strength does
Parasympathetics, gastrin, motilin increase frequency of AP, increases strength
Sympathetic, secretin, and GIP, decreases frequency of AP, and strength
• Caudad region contracts, drives chyme towards pyloric sphincter, but it is contracted.
Pyloric sphincter has minor tone which allows water to flow, but chunks cannot
• Retropropulsion: Contents pass back through contracted stomach. Allows grinding of food.
Forms an acidic chyme.
• Neural and endocrine influences at play

Emptying

• The degree of tension on the pyloric sphincter is modulated by neural and humoral signals
from both the stomach and duodenum
• Fat, and acid in duodenum inhibit gastric emptying
Regulates how much chyme ends up in duodenum
Regulating Gastric Emptying

• Gastric factors: Enhance emptying

Increased food volume causes distension of stomach walls

Local myenteric plexus reflexes mediates this

Gastrin released from the antral mucosa enhances emptying in stomach
• Duodenal factors: Inhibit emptying

Neural mechanisms

Distention, and irritation of the duodenum
Osmolality, and acidity of the chyme: Hyposmotic or hyperosmotic

Protein breakdown products
• Hormonal mechanisms: CCK and GIP inhibit gastric motility
Cholecystokinin (CCK): Inhibits gastric motility caused by gastrin
Gastric inhibitory peptide (GIP): Inhibits gastric motility, and releases insulin in pancreas
Stimulated by fats entering the duodenum since fats take long time to digest
Inhibiting gastric emptying while lipids are present allows digestion of lipids
• Stomach emptying rate regulated by gastric factors (promote it) and duodenal factors (inhibit it)
• Gastric motility inhibited by hormones (CCK) and (GIP)

Small intestine motility

• Segmented contractions and peristalsis mix digestive enzymes and pancreatic secretions
Expose nutrients to mucosa, and propel unabsorbed chyme
• Segmented contractions: Rings of contractions, pushed contents back and forth, mixing
• Peristalsis: Propels chyme along small intestine, and exposes it to epithelia of small intestine.
• Migrating myoelectric complexes (MMC): Waves of electrical activity sweep through intestines
during fasting. Trigger peristaltic waves which facilitate transport of indigestible material.

• Peristaltic rush: Starts at beginning of alimentary canal and rushes through its entire length.
Sweeps small intestines contents out within minutes. Occurs in infections, leads to diarrhea.
• Duodenum rate of contraction = 12 waves per minute
• Ileum rate of contraction = 9 waves per minute

Ileocecal Valve

• Gastroileal reflex: Pressure and irritants in ileum causes relaxation of sphincter (promote
peristalsis). Pressure/irritants in cecum causes contraction of sphincter (inhibit peristalsis)
• Ileocecal sphincter: Regulates large intestine influx. Valve-protrusion that extends into
cecum. Between ileum and cecum. Prevents colon back-flow.
Pressure in cecum, and sphincter contracting causes valve to close
• Cecum damage blocks emptying of ileum into cecum.
Large Intestine Motility

• Mixing (segmented contractions) = “Haustrations” (segmentation)

• Propulsion = “mass movements”
• Gastrocolic Reflex: Causes increased colon motility. Triggered by distension in the stomach
(mediated by CCK, gastrin) Long arc reflex.
Mediated by parasympathetics
• Gastrocolic reflex distension causes mass movements
Mass movements only occur 1-3 times per day
Mass movements propel contents into distal contents, and fecal contents enter rectum
• No digestion, instead absorb water and electrolytes to form solid feces. Stored until expelled
• Proximal half: Absorption takes place
• Distal half: Storage of feces
• Large intestine is slower than rest of GI tract, but motility patterns are similar (peristalsis,
segmentations)

Colon Movement

• Urge of defecation causes colon peristalsis, rectum contraction, and IAS relaxation
Defecation only occurs with relaxation of external anal sphincter
• Defecation reflex: Triggered by feces entering rectum. Intrinsic and extrinsic portions of reflex
which promote defecation.
Intrinsic: Mediated by ENS. Relatively weak, and only uses neurons within rectum
When feces enter, it causes stretch which activates ENS and triggers peristalsis
Intrinsic defecation reflex (myenteric plexus)
Extrinsic: Mediated by ANS. Relatively strong, and augments intrinsic activity
Parasympathetic defecation reflex (sacral spinal cord)
10.2 - GI Control

Types of Glands

1. Single cell glands: Goblet cells

2. Gastric pits (crypts of Lieberkühn): Opening of deeper glands

3. Tubular glands: Oxyntic glands, Brunners glands.

4. Complex glands: Salivary glands, pancreas, liver. Accessory structure glands.
Connected to alimentary canal via ducts
• Another source of secretion along alimentary canal are cells from epithelial lining.

General Principles

• Main secretions: 1. Digestive enzymes, 2. Mucus, 3. Water & electrolytes, 4. Digestive

hormones 

• 9 L of fluid passes through GI tract every single day
2 L from drinking fluid, and 7 L from GI tract itself. We don’t eliminate the 7 L
3.5 L comes from exocrine glands (salivary, pancreas, liver)
3.5 L comes from epithelial cells lining GI tract
• Volume in alimentary canal exceeds blood volume (5 L)

Digestive Enzymes

• Digestive enzymes are secreted from mouth all the way to ileum. Purpose is to undergo
digestive hydrolysis, liberate energy, and breakdown food into nutrients
• Cells that produce digestive enzymes (proteins) have robust ER, many mitochondria, and
secretory vesicles which cluster close to apical surface of epithelial cells

Mucus

• Source of mucus: Mucous cells (stomach) & Goblet cells (small intestine)
25% of cells in intestine are goblet cells

• Viscous adherent properties 

• Enough body to prevent contact of most food particles with tissue 

• Lubricates, and protects.

• Strongly resistant to enzymes in digestion
This prevents hard acid from damaging wall of organ

• Neutralizing properties which protect body. Buffering capacity due to bicarbonate.

• Present in the entire alimentary tract (mouth to anus)
• Made up glycoproteins
Water and Electrolytes

• Glands secrete them (water and electrolytes)

• Resting state of glandular cell: Vrest = -30 - -40 mV
• Neural stimulation causes influx of Cl-, hyperpolarization to -40 - -60 mV
• Na+ influx due to increased Cl- which restores Vrest but creates osmotic imbalance inside cell
• Osmotic force (πc) causes water to enter the cell which causes swelling
Water channels (aquaporins) allows bulk movement, water takes Na+ and Cl- with it.
• Process is very fast (~1 second)

Stimuli for Alimentary Tract Glands

1. Direct contact with food stimulates glands present in nearby region (localized effect)
Tactile, chemical, distension
True for mucus secretion as well
2. ENS: Detects different variables (pH) which regulate enzymes (glands), and mucus
3. ANS: Parasympathetic stimulates secretion, and sympathetics inhibit secretions
4. Hormones: Regulates composition and quantity of glandular secretions. Released when
food is present in gut, and carried by circulation. Digestive hormones are tightly regulated

Esophageal Secretion

• Esophagus does not secret enzymes, only mucus secretions present

• Esophagus has no protective walls similar to the stomach

Gastric Glands

• Gastric pit: Invagination which is opening for long tubular gland

• Two types of glands
1. Parietal (oxyntic) gland: Digest proteins, and triglycerides
Parietal cell: Secrete HCl, and intrinsic factor
Mucus neck cell: Secrete alkaline mucus, protects epithelium from HCl
Chief (peptic) cell: Secrete inactive enzyme called pepsinogen, and gastric lipase
Enterochromaffin-like cells: Secretes histamine (stimulates acid)
Enterochromaffin cells: Secretes ANP
D cell: Secretes somatostatin (inhibits acid)
Found in body of stomach (majority of digestion)
2. Pyloric gland: Similar structure but different location.
Mucus neck cell: Secrete alkaline mucus
D cell: Secretes somatostatin
G cells: Secrete gastrin (stimulates acid)
Enterochromaffin cells: Secretes ANP
Similar structure but different location.
Very few chief cells, and no parietal cells.
Clinical Correlate: Pernicious Anemia

• Intrinsic Factor: Necessary for vitamin B12 absorption into blood


Coded by GIF gene
Receptors for intrinsic factor on ileum epithelium
• Vitamin B12 deficiency leads to anemia (not enough mature RBC)

• Autoimmune disease directed against IF or parietal cells
Not enough red blood cells are present due to lack of vitamin B12
• B12 necessary for maturation of RBC
• Pernicious anaemia: Rare form of anemia where there is a deficiency in intrinsic factor
Without intrinsic factor, body can not absorb B12. Treatment is boosting B12 injections
Left untreated, it causes neurological symptoms like poor reflexes, confusion

Gastric Secretions - Parietal Cells and HCl

• Canaliculus: Ruffled surface with microvilli present in parietal cells.

Contains 160 mM HCl per L —> pH < 1
• Basolateral: Na-K ATPase, HCO3-Cl exchanger, and chloride channel
• Apical: H-K Exchanger (active transport), potassium and chloride channels, sodium carrier
• CO2 and H2O freely enter and leave cell
• CO2 + H2O <—> H2CO3 <—> H+ + HCO3- occurring in parietal cell
• Forward reaction favored since proton pump extrudes H+, and exchanger extrudes HCO3-
• H-K exchanger and Na-K both pump K+ into the cell
• Cl- flows to lumen of canaliculus since H+ is being pumped into it
This creates an osmotic gradient which forces water to flow into lumen

Gastric Secretions - Other cells of the oxyntic gland

• Parietal cell stimulated by ACh, Histamine, Gastrin.

Inhibited by Somatostatin
Higher pH inhibits somatostatin
• Gastrin —(+)—> chief, ECL, and oxyntic cells
• Somatostatin —(-)—> parietal cells, ELC cells, and G cells
• ECL —(+)—> parietal cells
• Amount of acid is a balance between inhibitory/stimulants of acid
Gastric Secretions - Parietal Cells and HCl

• Potentiation: the ability of two stimuli to produce a combined response that is greater than the
sum of the individual responses. Synergy.
• Two different messenger systems produce a greater response than single system
• Synaptic transmission: ACh target M3 on parietal cells (G𝛼q), stimulates H-K ATPase.
Inhibited by Atropine. Bad plan since it targets many M receptors.
• Paracrine communication: Histamine binds to H2 (G𝛼s), stimulates H-K. Inhibited by
cimetidine.
• Endocrine communication: Gastrin binds to CCKB receptors (G𝛼q).
• Somatostatin, and prostaglandins are coupled to G𝛼i
• Proton secretion is regulated by three independent agents: ACh, Histamine, Gastrin
Interactions between these three impact how much H+ is secreted
• Omeprazole inhibits H-K ATPase which indirectly blocks all three agents
Very effective for excess acid (GastroEsophageal Reflux Disease)

Activation of pepsinogen

• ACh produced by ENS and vagus nerve

• ACh stimulates chief cells for pepsinogen. But secretion depends on HCl from parietal cells
• HCl cleaves pepsinogen into pepsin
Two step process (Pepsinogen releases, then HCl release)

Phases of Gastric Secretions

1. Cephalic Phase: Starts before eating. Sight/smell/thinking about food. Hungrier = more
intense stimulation. No food present so originates in cerebral cortex, transmitted to stomach
via vagus nerve. 3% of gastric secretions occur in preparation for food. Stimulates mucus
cells, chief cells, parietal cells, G cells. Activation of submucosal plexus. Stage is brief.
2. Gastric Phase: Food enters stomach. Further stimulation of mucus, chief, parietal, and G
cells. Food buffers pH which removes inhibitory effect of somatostatin which promotes a lot
of HCl. Activation of myenteric plexus. Mixing. Long stage (as long as food is present)
3. Intestinal Phase: Chyme enters small intestine (duodenum). Inhibitory phase. Duodenum
slows down gastric emptying. Neural and endocrine responses. Stretch and chemoreceptors
(pH, osmolarity). Small intestine feeds back into myenteric plexus via enterogastric reflex to
slow it down. CCK, GIP, Secretin travels via portal which inhibits chief, and parietal cell.
Pancreatic Digestive Enzymes

• Endocrine portion: Islets of Langerhans (15%)

• Exocrine portion: Acinar cells and its associated draining duct (85% of organ)
• Acinar cells: Secrete digestive enzymes within pancreas. Highest rate of protein synthesis.
Cells coupled via gap junctions. Allows discharge of massive amounts of zymogen
Tight junctions at apex to prevent leakage of zymogen between other acinar cells
• Zymogen: Inactive form of enzyme that digestive enzymes are synthesized as because they
are so powerful. Undergoes exocytosis to reach lumen of duct
• Epithelia cells lining the ducts: Secrete watery bicarbonate solution which travels into main
pancreatic duct and pass through duodenum via sphincter of Oddi

Regulation of Exocytosis from Acinar Cells

• Pancreatic juice: Digestive enzymes, bicarbonate, and water.

• Zymogen granules are plentiful in apical half of cell, waiting to be discharged.
• Stimulates zymogen exocytosis: Gastrin-releasing peptide (GRP), cholecystokinin (CCK),
acetylcholine (ACh), Secretin, vasoactive intestinal polypeptide (VIP)
Acinar cell has receptors for all 5 agents
• GRP, CCK, ACh coupled to G𝛼q —> Ca
• Secretin, and VIP coupled to G𝛼s —> cAMP
• Calcium spikes are simultaneous (gap junctions) results in burst of zymogen

Pancreatic Digestive Enzymes

• Enterokinase: Enzyme at surface of epithelial duodenum cells which converts trypsinogen

into trypsin. Active trypsin can activate itself
• Trypsin: Activates trypsinogen, chymotrypsinogen, and procarboxypeptidase (zymogens).
Most important enzyme.
• All three enzymes in active form continue protein digestion
• Acinar also secrets trypsin inhibitor which forms stable complex with trypsin, and inactivates
auto-catalytically activated trypsin. This is essential. 56-amino acid peptide.
• Pancreatitis: Breakdown of protective mechanisms. Caused by damage or blockage.
Causes disruption of trypsin inhibitor
Three enzymes left uninhibited will consume the pancreas. Reduces circulatory shock.

Enzymes of Pancreas

• Enzymes of pancreas are essentially proteases

• Endopeptidases: Cleave protein within interior which produces peptide fragments
• Exopeptidases: Cleaves at protein at exterior (NH2, or COOH)
Capable of cleaving individual amino acids.
• Pancreatic enzymes: Trypsin, chymotrypsin, carboxypeptidase, pancreatic amylase,
pancreatic lipase, cholesterol esterase, and phospholipase.
• Pancreatic amylase is alkaline instead of the acidic type in the mouth
• Pancreatic lipase is alkaline which hydrolyzes lipids. Different than mouth and stomach lipase
Pancreatic Secretions - Bicarbonate and Ductule Cells

• Pancreas secretes bicarbonate which neutralizes acidic chyme in the duodenum

• Pancreas also secrets water to flush substances (zymogens, bicarbonate) into duodenum
• Apical domain: Active transporter for bicarbonate, and Na+ channel
• Basolateral domain: Na+-H exchanger (active transport)
• CO2 and H2O freely enter and leave cell
• CO2 + H2O —> H2CO3 —> H+ + HCO3-
• Forward reaction favored since H+ extruded in blood instead of lumen. HCO3- extruded in
lumen instead of interstitial. Na+ follows to neutralize solution. Water follows by osmotic gradient

Three Elements of Pancreatic Secretion Regulation

1. Secretin: Made by S cells in epithelium lining the duodenum (crypts of Lieberkühn)

Stimulates epithelial cells in ducts. In absence of it, enzymes stuck within the ducts

Stored in an inactive form
Released triggered by acid in stomach

Travels in blood stream and stimulates pancreas
Pancreas then secretes large quantities of water with high bicarbonate concentration

pH of 4.5-5.0 triggers release, but release enhanced when the pH drops to 3.0
27 amino acid polypeptide.
2. CCK: Secreted from the I cells in the mucosa of the duodenum and upper jejunum
Stimulates secretion of pancreatic digestive enzymes from the acinar cells

Partial breakdown products of proteins and long-chain fatty acids triggers release

Accounts for almost 70-80% of the total secretion of pancreatic digestive enzymes
33 amino acid polypeptide.
3. Acetylcholine: Parasympathetics and ENS. Works with CCK to regulate secretion of
pancreatic zymogens. Releases enzymes into acini.

Phases of Pancreatic Secretions

• HCl + NaHCO3 —> NaCl + H2CO3 —> H+ + HCO3- + NaCl

• Pancreas has phases similar to stomach
1. Cephalic phase: Starts before eating. Originates in cerebral cortex, transmitted via vagus
nerve. ACh released so only small amount of water and bicarbonate produced.
2. Gastric phase: Same time as gastric phase in stomach. Vagus nerve sends information to
reinforce cephalic phase. Still only water and bicarbonate since only ACh present
3. Intestinal phase: Chyme enters duodenum, secretin is released which further stimulates
epithelia cells. CCK release reinforces effect and releases enzymes.
Liver - Overview and Secretory Function

• General functions: Very versatile organ, but focus on role in digestion

Screens nutrients, toxins, and other substances delivered from the digestive tract 

Stores, processes, and passes them back to the blood 

Produces plasma proteins 

Breaks down old blood cells, and fats 

Regulates blood sugar levels, and protein metabolism 

Converts ammonia to urea 

• Bile: Combination of proteins (globular), lipids, carbohydrates, vitamins, and minerals.
Important in fat digestion and absorption
Excretion of important waste products: Bilirubin (waste), and excess cholesterol
• Bile acids: Emulsifies large fat droplets, and aids in lipid absorption
• Emulsification: Breakdown of fat droplets into smaller droplets which maximizes surface area.

Liver - Bile

• Secreted in two steps

1. Hepatocytes secret bile into bile canaliculus
Organized into plates of tissue which surround bile canaliculi (tubular structure)
2. Secretin stimulates epithelia which secrets water/H2CO3 and allows bile to flow



Secretory Functions - Gall bladder

• Liver releases bile —> Hepatic duct —> Cystic duct —> Gallbladder (storage)
• Gallbladder: Contains storage capacity (50mL). Epithelium site of active Na+ transport, which
concentrates solution.
• Gallbladder stimulation —> Secretes bile —> Cystic duct —> Common bile duct —>
Pancreatic duct —> Sphincter of Oddi
• Gall-stones: Produced in liver, and gallbladder. Caused by absorbing too much water from
bile, too much bile acids from bile, too much cholesterol in bile, and epithelium inflammation
• Risk factors: Women due to estrogen increasing cholesterol in bile, People over 40, family
history (genetics), Native Americans, obesity, and fasting. Main thing is elevated
cholesterol. Diet is important.

Secretory Functions - Liver and Gall bladder

• Bile flow lowest during fasting, and any bile produced is diverted to gallbladder.
• Once chyme enters duodenum, CCK and secretin production is stimulated.
• CCK stimulates contraction of gallbladder, and relaxes sphincter of Oddi (strongest)
Forces bile into cystic duct
• ACh also stimulates gallbladder contractions (weaker stimulus)
• Secretin stimulates water, and bicarbonate to flush bile
Secretory Functions - Small Intestine

• Small intestine marks digestion completion, and absorption initiation

• Components of small intestine increase surface area. They are large circular folds (valvuae
connevente), villi, and microvilli.
• Villi: Finger like projections which contain their own capillary bed, and lacteal.
In-between villi are crypts
• Microvilli (brush border): Covers villi apical surface. Packed with transporters, and carriers
• Enterocytes secret specific enzymes for macronutrients
• Proteins —> Peptidase
• Carbohydrates —> Disaccharidases (Sucrase, Maltase, Isomaltase, Lactase)
• Lipids —> Intestinal lipase (splits fats into glycerol and fatty acids)
• These are all regulated by local reflexes (presence of food, tactile, irritation)

Small Intestine - Brunner’s Glands

• Brunner’s Glands: Array of mucus glands which secret alkaline mucus in response to tactile,
irritating, vagal stimuli, secretin. Inhibited by sympathetics. Glassy appearance. Between
pyloric sphincter and sphincter of Oddi.
Constant stress inhibits this which damages duodenum. Source of peptic ulcer.
• Alkaline mucus needed to prevent irritation of duodenum

Small Intestine - Crypts of Lieberkühn

• Crypts of Lieberkühn: Contains goblet cells, paneth cells, enterocytes, and epithelia
• Enterocytes: Produces water and electrolytes (similar to extracellular fluid) which are rapidly
reabsorbed by neighboring villi. Helps wash intestinal contents over absorptive surface.
• Paneth cells: Secret anti-microbial compounds (defensins, lysozymes)

Small Intestine - Apical and Basolateral Domain

• Enterocytes contain apical and basolateral domain with different channels

• Apical domain: CFTR channel, gated by cAMP. When open, Cl extruded into lumen
• Basolateral domain: Na-K-Cl transporter (2 Cl for 1 Na, 1K). Na-K ATPase, K channel
• Chloride enters from basolateral but leaves through apical
• Na travels through paracellular pathway to neutralize charge in lumen
Solutes in lumen drag water by osmosis
• Mechanism of enterocytes
• Similar to mechanism of cholera
G proteins and disease: Effect of Cholera toxin

• G𝛼s is the target of toxin liberated by Vibrio cholerae, bacterium that causes Cholera. Binding
of cholera toxin to G𝛼S keeps it turned on, resulting in high cAMP levels, causes massive
salt loss from cells in intestinal epithelium, water follows by osmosis, causing hypertonicity
• Basolateral contains Na+-K+ ATPase and transporter (brings 1 Na+, 2 Cl-, and 1 K+ in)
Na+ leaves cell via Na+-K+ ATPase in basolateral
K+ leaves via ion channels in basolateral
Cl- leaves via Chlorine channel (CFTR) expressed only in apical surface
• CTFR tightly regulated by cAMP levels, cAMP opens it, allowing Cl- to leave
• When Cholera infects cells, cAMP is high, CFTR constantly pumps Cl- into intestine lumen
• Na+ typically leaks across epithelium (through tight junction) in order to form electrically neutral
solution. All solute is in lumen, water follows by osmosis, leading to diarrhea

Secretory Functions - Large Intestine

• No digestion occurring, therefore no villi. However still contains crypts of lieberkühn

• Mucus is the principle secretion, some bicarbonate and water
• Site for water absorption as fecal matter is being formed
• Parasympathetic stimulation of pelvic nerve increases mucus secretion and motility
10.3 - Nutrient Digestion and Absorption

Carbohydrate Digestion - Overview

• All of carbs taken in are either large polysaccharides or disaccharides

• Starches are digestible polysaccharides (𝛼-linkage)
• Cellulose are indigestible polysaccharides. Referred to as fiber, not a source of nutrition (𝛽)
Human body lacks necessary enzyme to cleave bond
• Disaccharides bonded by glycosidic bond
Most common are lactose, sucrose, and maltose
• Lactose: Glucose + galactose (lactase)
• Sucrose: Glucose + fructose (sucrase)
• Maltose: Glucose + glucose (maltase)
• Polysaccharides broken down into disaccharides by generic enzyme (amylase)
• Disaccharides broken down into monosaccharides by specific enzymes (-ase)
• Most common sugar in diet is glucose, therefore digestion revolves around it

Carbohydrate Digestion - Pathway

• Oral cavity, pharynx, esophagus: Polysaccharide digestion begins here via salivary
amylase which breaks it into maltoses. Disaccharides not digested.
• Stomach: No carbohydrate digestion
• Small intestine (lumen): Polysaccharides continue digestion via pancreatic amylase
• Small intestine (epithelium): Disaccharides digestion begins here via disaccharidases
(specific enzymes). Final stage of digestion and absorption.
• Human body can absorb only monosaccharides, not poly- or disaccharides.

Protein Digestion - Overview

• Protein made up of amino acids linked by peptide bonds via a condensation reaction
• Digestion of protein occurs via hydrolysis by hydrolytic enzymes
• Proteases are endopeptidase or endopeptidase
Endopeptidase: Breaks internal peptide bonds (Trypsin, Chymotrypsin)
Exopeptidase: Breaks end peptide bonds
Aminopeptidase: Cleave at amino terminus
Carboxypeptidase: Cleave at carboxyl terminus
Dipeptidase: Acts chains of two amino acids
• Trypsin: Serine protease that cleaves polypeptide chains at the carboxyl side of amino acids
lysine or arginine

• Chymotrypsin: Cleaves peptide bonds with an aromatic carboxyl terminal, such as tyrosine,
tryptophan, or phenylalanine
Protein Digestion - Pathway

• Stomach: Protein digestion begins here via pepsin which is secreted by chief cells
Renin is produced by infants, and breaks down breast milk products
• Small intestine (lumen): Contains pancreatic trypsin, chymotrypsin, and carboxypeptidase
• Small intestine (epithelium): Contains dipeptidase, carboxypeptidase, aminopeptidase

Fat Digestion - Overview

• Dietary lipids obtained from both plants and animals

• Most fats in diet are triglycerides which are broken down by two acidic lipases
• Lingual lipase: Cleaves off single fatty acid, leaving it with a diacylglycerol, and one free FA
• Gastric lipase: Cleaves off single fatty acid, leaving it with a diacylglycerol, and one free FA
• Bile salts: Emulsifies lipids to increase surface area for lipase breakdown.
• Pancreatic lipase: Cleaves all three fatty acids from glycerol.

Fat Digestion - Pathway

• Oral cavity: Fat digestion begins here via lingual lipase in saliva
• Stomach: Contains gastric lipase which produces fat globules
• Small intestine (lumen): Contains bile salts which produce fat droplets and pancreatic lipase

Nucleic Acid Digestion - Overview

• When diet contains cells (plants or animal), this means we ingest nucleic acids
• Nucleotide: Sugar (ribose), nitrogenous base, and phosphate group.
• Nucleoside: Sugar (ribose) and nitrogenous base.
• Nucleases: Cleaves RNA, and DNA into nucleotides.
• Nucleotidases: Break down nucleotides into nucleoside and phosphate group.
• Nucleosidases: Breaks down nucleosides into sugar and base.

Nucleic Acid Digestion - Pathway

• Small intestine (lumen): Nucleic acid digestion begins here via pancreatic nucleases
• Small intestine (epithelium): Contains nucleotidases, nucleosidases, and phosphatases
Absorption - Overview

• Once macromolecules are broken down, nutrients are absorbable

• Absorption utilizes five processes
1. Active transport: Transport dependent on energy, not solute concentration.

2. Passive diffusion: Linear relationship between rate and solute concentration.

3. Facilitated diffusion: Exponential until equilibrium between rate and solute concentration.

4. Secondary active transport: Co-transport. Exploitation of gradient.
5. Endocytosis: Taking in molecules via invagination forming vesicle
• High permeability: Hydrophobic molecules (O2, CO2, N2, Steroid hormones (Testosterone,
Cortisol, Estrogen)
• Medium permeability: Small uncharged, Hydrophilic molecules (H2O, Urea, Glycerol)
• Low permeability: Large uncharged, Hydrophilic molecules (Glucose, Sucrose)
• No permeability: Ions, charged (H+, Na+, K+, Ca2+, Cl-, Mg2+, HCO3-)
• Less associated with water = more permeable, and Larger and polar = less permeable

Absorption - Anatomy Overview

• Most absorption takes place small intestine, however some in stomach (only alcohol and
acidic things)
• Absorption occurs by same components that increase surface area
Circular folds (valvulae conniventes), villi, and microvilli
• Total amount of fluid that needs to be absorbed each day equal to ingested fluid (1.5L) and
secreted digestive fluids (7.0L) for (Total = 8.5L). 7.0L reabsorbed, and 1.5L excreted

Absorption - Villi Anatomy

• Mucosa: Blood capillary surrounds lacteal, Lamina propria, Muscularis mucosae

Intestinal gland (crypt of Lieberkühn): Produces secretin, CCK, lysozyme
• Submucosa: Lymph vessels, arteriole, and venule
• Microvilli: Brush-border. Packed with proteins (transporters, carriers, vesicles, and enzymes)
Pinocytic vesicles: Facilitate absorption of water
Absorption - Proteins

• Two sources of proteins: 1. Ingested (dietary or exogenous) (50%), and 2. Endogenous

which is made up of secreted proteins (enzymes, hormones, Ig) (50%)
• Absorption is limited to mono, di-, or tripeptides
Body can not absorb proteins larger than 3 amino acids
Rarely, large proteins absorbed (during perinatal period, infant absorbs Ig via milk)
• Amino acids transport via primary or secondary active transport
• Di/tripeptides transport via secondary active transport
• Na-AA transporter: Transports single amino acids. Four subtypes based on amino acid
categories. Binds amino acid after Na binding.
• PepT1 transporter: Transports di-/tripeptides via proton (H+) gradient. Further broken down in
enterocyte cytoplasm by peptidases
• Amino acids exit from basolateral membrane of enterocyte via 6 classes of transporters
1. System A: Na+ dependent transport of neutral amino acids
2. GLYT1 system: Na+ and Cl- coupled transport of glycine
3. System y+: Na+ independent transport of cationic amino acids (lysine, arginine, ornithine)

4. System L: major Na+ independent transport of neutral amino acids (LAT+)

5. System y+L: Exchange system whereby cationic amino acids are exchanged for Na+
coupled entry of neutral amino acids from blood. Works with y+ and L system.

6. System Asc: Na+ independent transport of short chain amino acids (glycine, alanine,
serine, cysteine, threonine)

Absorption - Fats

• Digested fatty acids and glycerol dissolve into bile which form bile micelles
• Bile micelles: Fat droplets covered in bile salt. Carries fat to brush border
Dissolvable in the chyme
• Once at brush-border, lipids partition across lipid bilayer into enterocyte
Bile salt re-enter chyme to form additional micelles
• Lipid components are directed to ER, and smooth ER recreates triglycerides
• Golgi apparatus attaches protein to triglyceride to form chylomicron
Due to protein, chylomicrons are not lipid-soluble
• Chylomicrons enter secretory vesicles at basolateral which enters lacteal
• Xenical which inhibits pancreatic lipase reduces digestion of lipids, and therefore prevents
fat absorption which leaves it behind in secretions. Side effect leads to sudden fatty-diarrhea
Absorption - Carbohydrates

• Carbs broken down mainly to monosaccharides, and only few disaccharides can be digested
Left with glucose, galactose, and fructose (mono)
• SGLUT-1: Na+ transporter moves glucose and galactose via secondary active transport.
• GLUT-5: Transports fructose via facilitated diffusion (capable of saturation). Any fructose
that can’t digest gets eliminated, water doesnt get reabsorbed which leads to diarrhea via fruit.
• Na and glucose accompanied by 260 water molecules (osmotic pressure), responsible for 5 L
• Reduced osmolarity solution administered to cholera patients (oral rehydration)
• GLUT-2: Transport sugar from basolateral by facilitated diffusion which is Na+ independent
• Important dietary carbs include starch and disaccharides (lactose and sucrose) 

• The final enzymatic digestion that liberates monosaccharides is conducted by enzymes that
are tethered in lumenal plasma membrane of absorptive enterocytes (brush-border hydrolyases)

• Glucose generated by digestion of starch or lactose is absorbed in the small intestine only by
cotransport with sodium which has exceptionally important implications in medicine.

Absorption - Water and Electrolytes

• Water always moves passively (osmosis)

• When chyme is diluted then water is absorbed into epithelium by osmosis. Water can be
moved in both directions
• Reverse osmosis occurs with hypertonic solutions in duodenum (colonoscopy preparation
which initiates diarrhea)
• Water travels via transcellular (aquaporins), and paracellular pathways according to osmotic
gradients from electrolyte concentrations.

Absorption - Summary

• Absorption largely dependent on Na-K ATPase (cardiotonic steroids (digitalis) and Ouabain)
• Aldosterone increases sodium recovery from renal tubules, secreted during dehydration. It
also increases sodium reabsorption from the gut. Cl comes with Na mostly passively.
• Once out of enterocytes, it enters interstitial fluid of individual villi. Any water soluble
products are transported by hepatic portal vein which enters liver. This regulates distribution of
nutrients to body, and also detoxifies them
• Chylomicrons travel through lacteals and returning to systemic circulation via left subclavian



Large Intestine

• Large intestine: Cecum —> Ascending —> Transverse —> Descending —> Sigmoid colon
• Large intestine is specialized for water reabsorption which remains in alimentary canal (5-8L
of water and accompanying electrolytes). Important in formation of feces.
• Very tight junctions between enterocytes to prevent back diffusion. As solid fecal matter
forms, it present strong osmotic force but tight junctions prevent water going back into feces.
Learning objectives (Unit 10):

1. Describe the stages of food processing with an understanding of where each phase
takes place

1. Ingestion: Oral cavity.

2. Digestion: Two types. Liberates absorbable nutrients. Stomach

2a. Mechanical: Food ground, cut, and dissembled

2b. Chemical: Enzymatic hydrolysis of food, splits bonds.

3. Absorption: Nutrients enter body cells. Small intestine.

4. Elimination: Anything that remains behind in GI tract, undigestible material. Rectum.

2. Identify the components of the alimentary canal and the accessory glands

Alimentary canal: Mouth —> Pharynx —> UES —> LES —> Esophagus —> Stomach —>
Pyloric sphincter —> Duodenum —> Sphincter of Oddi —> Jejunum —> Ileum —> Ileocecal
valve —> Cecum —> Large intestine —> Rectum —> IAS —> EAS —> Anus

Accessory structures: Salivary glands, pancreas, liver, gall bladder. Connected by ducts.

3. Describe the structure and function of the enteric nervous system. How is it modulated
by the ANS?

ENS: Intrinsic regulation of the GI tract at myenteric, and submucosal plexus. Three lengths.

1. Short length reflexes: Within the gut wall. Controls secretion, mixing, local effects.

2. Medium length reflexes: Extend from gut wall to the prevertebral sympathetic ganglia which
project back to the GI tract. Links two segments of GI tract (i.e. enterogastric reflex)

3. Long length reflexes: Extend from gut to the spinal cord or brain stem and back to the gut.
Controls motor and secretion functions. Many pain reflexes. General inhibitory effect.

ANS: Provides extrinsic regulation of the GI tract. Influences ENS through both sympathetic
(fight-or-flight) which transmit NE, and parasympathetic (rest-and-digest) which transmit ACh,
Substance P, or Vasoactive inhibitory peptide (VIP).

4. Identify the three types of reflexes that modulate GI motility and secretion. Where do
they originate? What signals initiate the reflexes?

1. Gastroileal reflex: Pressure and irritants in ileum causes relaxation of sphincter (promote
peristalsis). Pressure and irritants in cecum causes contraction of sphincter (inhibit peristalsis).

2. Gastrocolic reflex: Causes increased colon motility, and mass movements. Triggered by
distension in the stomach. Entire reflex mediated by the parasympathetic nervous system.
Efferent limb mediated by CCK and gastrin. Long reflex arc.

3. Defecation reflex: Causes colon peristalsis, rectum contraction, and IAS relaxation. Triggered
by feces entering rectum. Intrinsic portion (myenteric plexus) mediated by ENS is weak.
Extrinsic portion (sacral spinal cord) mediated by parasympathetics is strong, and augments
intrinsic portion. Conscious control needed to relax EAS.

5. Describe the types of movements/motility that occur at each point along the GI tract

1. Peristalsis: Propulsions. Mass movements. Uniform across alimentary track.

Retropropulsion. Stimulated by distension of wall, food for digestion, and increased
parasympathetic tone. Each segment has each unique frequency, parasympathetics increase
strength, not rate.

2. Segmentation: Haustrations. Mixing. Segmented contractions. Stimulated by

parasympathetics, gastrin, and motilin. Inhibited by sympathetics, secretin, and GIP.

3. Receptive relaxation: Allows accommodation of food by vagovagal reflex. Triggered by

stomach wall stretch. Causes relaxation of smooth muscle in stomach. NT is VIP.

4. Gastric emptying: Enhanced by gastric factors (gastrin), and motilin released by wall
distension. Inhibited by duodenal factors released by distention, irritation, osmolarity, acidity,
protein breakdown. Also inhibited by hormones (CCK, GIP, Secretin)

6. Identify the secretory functions of the GI tract. What stimulates secretion from the GI
epithelium?

Direct contact with food stimulates glands (tactile, chemical, distension)

ENS: Detects variables (PaO2, PaCO2, pH) which regulate secretions.

Sympathetics: Inhibit secretions

Parasympathetics: Stimulate secretions.

Hormones: Regulate composition/quantity of secretions. Released when food present in gut.

7. Describe the cells and glands that produce secretions along the length of the GI tract.
Include: a. Gastric glands (all the cell types) b. Pancreas (all enzymes), c. Liver, d. Small
intestine, e. Large intestine

Parietal glands: Parietal cell (HCl, intrinsic factor), mucus neck cell (mucus, bicarbonate), chief
cells (pepsinogen, gastric lipase), ELC (histamine), EC (ANP), and D cell (somatostatin).

Pyloric glands: Mucus neck cell (mucus, bicarbonate), EC (ANP), D cell (somatostatin), and G
cell (Gastrin).

Pancreas: Acinar cells (Trypsin, trypsin inhibitor, chymotrypsin, pancreatic amylase, pancreatic
lipase, cholesterol esterase, phospholipase)

Liver: Parenchymal hepatocytes (Bile)

Small intestine: Goblet cells (mucus), Paneth cells (defensins, lysozyme), brunners glands
(alkaline mucus), enterocytes (peptidase, sucrase, maltase, isomaltase, lactase, intestinal
lipase), S cells (Secretin), I cells (CCK)

Large intestine: Goblet cells (mucus), brunners glands (alkaline mucus), Paneth cells (defensins,
lysozyme)

8. What are the phases of secretion?

1. Gastric

A. Cephalic phase: Begins before eating. Sight/smell/thinking. Hungrier = more intense. No

food present. Originates in cerebral cortex, transmitted via vagus nerve. Stimulates mucus
cells, chief cells, parietal cells, G cells. Activation of submucosal plexus. Brief.

B. Gastric phase: Food enters stomach. Further stimulation of previous cells. Food buffers pH,
removes somatostatin which promotes HCl. Activation of myenteric plexus. Mixing. Long.

C. Intestinal phase: Chyme enters duodenum. Inhibitory phase. Slows down gastric emptying.
Neural and endocrine responses. Stretch and chemoreceptors (pH, osmolarity). Feeds back
into myenteric plexus via enterogastric reflex. CCK, GIP, Secretin inhibits chief, and parietals.

2. Pancreas

A. Cephalic phase: Vagus nerve so only water and bicarbonate. Same as other cephalic phase.

B. Gastric phase: Vagus nerve so only water and bicarbonate. Same as other cephalic phase.

C. Intestinal phase: Secretin, CCK released from small intestine and stimulates pancreas.

9. Describe how each of the following are digested and absorbed: Carbohydrates,
Proteins, Fats, and Nucleic acids

Carbohydrates: Salivary amylase (oral cavity), pancreatic amylase (lumen small intestine), and
disaccharidases (epithelium small intestine). Glucose and galactose enter using SGLUT-1
which is secondary active transport via Na+. Fructose enter using GLUT-5 which employs
facilitated diffusion. All sugar leaves using GLUT-2 which employs facilitated diffusion.

Proteins: Pepsin (stomach), pancreatic trypsin, chymotrypsin, carboxypeptidase (lumen small

intestine), and dipeptidases, carboxypeptidase, aminopeptidase (epithelium small intestine).
Amino acids enter using active transport or secondary active with Na-AA exchanger. Di-/
tripeptides enter using PepT1 which employs secondary active transport via H+ gradient.
Amino acids exit using systems A, GLYT1, y+, L, y+L, Asc. A is Na+ dependent of neutral AA.
GLYT1 is Na+ Cl- transport of glycine. y+ transports cationic AA. L transports neutral AA. y+L
cationic exchanged for neutral. Asc transport short chain.

Fats: Lingual lipase (oral cavity), gastric lipase (stomach), and bile salts, pancreatic lipase
(lumen small intestine). Fatty acids enter via diffusion. Fatty acids enter smooth ER to reform
triglyceride then move to Golgi to form chylomicrons. They leave via endocytosis.

Nucleic acids: Pancreatic nuclease (lumen small intestine), and nucleotidases, nucleosidases,
and phosphatases (epithelium small intestine).

 EXAM 4 - (4/9)

Course information

• TA email: [email protected]

Questions:

Things to do before exam:

Notes:

• ALWAYS CHECK UNITS!!!!!!!!! NO MATTER WHAT!!!!!! FUCK YOU.

• Take a deep breathe and think you fucking retard.
• Get prepared EARLIER
• Get prepared early, but also memorize earlier too. Don’t wait till last day to memorize