Cell Injury, Death,

Inflammation, and Repair

J. Matthew Velkey
[email protected]
454A Davison, Duke South (green zone)
 Cellular Adaptation to Injury or Stress

Injury or Stress Adaptation

Increased demand Hyperplasia or hypertrophy

Decreased stimulation or lack Atrophy

of nutrients

Chronic irritation Metaplasia

Adapted - Normal - Injured
Cells
 Adaptations

• Hypertrophy
• Hyperplasia
• Atrophy
• Metaplasia
 Hypertrophy

Increase in the size of cells results

in increased size of the organ

May be Physiologic or Pathologic

 Examples of Physiologic Hypertrophy

Increased workload - skeletal muscle

cardiac muscle

Hormone induced –pregnant uterus

 Physiologic hypertrophy
Gravid uterus and Normal uterus
 Hyperplasia

Increase in the number of cells

results in increase in size of the
organ.

May be Physiologic or Pathologic.

 Physiologic Hyperplasia

• Hormonal hyperplasia
Female breast; puberty and pregnancy
• Compensatory hyperplasia
Prometheus
Unilateral nephrectomy
Erythroid hyperplasia of bone marrow
in chronic hypoxia (mountain climbers).
 Pathologic Hyperplasia

• Excessive hormone stimulation

Endometrial hyperplasia
Prostatic hyperplasia
• Viral infections
Papilloma virus (warts)
 Atrophy
• Reduced size of an organ due to a decrease in
cell size and number.
• Physiologic atrophy – notochord, post
partum uterus
• Pathologic atrophy – local or generalized
 Causes and Examples of Atrophy

• Decreased workload (disuse atrophy)

• Loss of innervation (denervation atrophy)
• Diminished blood supply (ischemia)
• Inadequate nutrition (marasmus, cachexia)
• Loss of endocrine stimulation (menopause)
• Aging (senile atrophy)
• Pressure (enlarging benign tumor)
Normal Atrophy
 Metaplasia
Reversible change in which one differentiated
cell type (epithelial or mesenchymal) is
replaced by another cell type.
Usually occurs in response to stress or chronic
irritation.
 Causes and Examples of Metaplasia

• Tobacco smoke - Squamous metaplasia in the

respiratory tract, most common.
• Gastric acid reflux - Gastric metaplasia of distal
esophagus; Barrett esophagus.
• Repeated skeletal muscle injury with
hemorrhage- muscle replaced by bone; myositis
ossificans.
Bronchus with Columnar to Squamous
Metaplasia
Esophagus with Squamous to Columnar
metaplasia
 Mechanisms of Metaplasia
• Re-programing of stem cells that exist in
normal tissue.
• Induced by cytokines, growth factors and
other environmental signals
• Retinoic acid may play a role.
• Exact mechanism is unknown.
 Cell Injury and Death
• Reversible – reduced ATP, cellular swelling
• Irreversible – two types of cell death
Necrosis – always pathologic
Apoptosis – may be physiologic
or pathologic
Necrosis vs. Apoptosis
 Causes of Cell Injury
• Oxygen deprivation (hypoxia or ischemia)
• Physical Agents (trauma)
• Chemical agents and Drugs
• Infectious Agents
• Immunologic Reactions
• Genetic Derangements
• Nutritional Imbalances
Reversible and Irreversible Cell Injury
 Reversible and Irreversible Cell Injury
normal kidney tubules reversibly injured irreversibly injured
kidney tubules kidney tubules

• Chromatin clumping • Nuclear fragmentation and

• Membrane blebbing loss
• Swelling of ER and • Membrane disintegration
mitochondria (slight • Swelling and rupture of ER,
eosinophilia) mitochondria, & lysosomes
(marked eosinophilia)
 Morphologic Alterations in Irreversible Injury
(Necrosis)
Cytoplasmic
Eosinophilia – denatured proteins and whorls of cytoplasm (myelin figures) stain strongly with eosin. Also,
loss of ribosomes decreases overall basophilia.

Nuclear (3 patterns)
Karyolysis - nucleus becomes pale
and eventually disappears

Pyknosis - nucleus shrinks,

chromatin condenses, becomes
deeply basophilic

Karyorrhexis – nucleus undergoes

fragmentation

These nuclear patterns may occur

together or separately and not
necessarily in any particular order.
Regardless of the pattern(s) observed,
the net result is that nuclei in dead cells
completely disappear after 1-2 days.
Patterns of Tissue Necrosis

Coagulative Necrosis
Liquefactive Necrosis
Fat Necrosis
Caseous Necrosis
Fibrinoid Necrosis
 Coagulative Necrosis
Pattern of cell death characterized by progressive loss of cell structure,
with coagulation of cellular constituents and persistence of cellular
outlines for a period of time, often until inflammatory cells arrive and
degrade the remnants.
Myocardial infarction:
another example of
coagulative necrosis
 Liquefactive Necrosis
Pattern of cell death characterized by dissolution of
necrotic cells.

Typically seen in an abscess where there are large

numbers of neutrophils present, which release
hydrolytic enzymes that break down the dead cells
so rapidly that pus forms.

Pus is the liquefied remnants of dead cells, including

dead neutrophils.
 KIDNEY

Coagulative Necrosis Liquefactive Necrosis

 Caseous Necrosis
The pattern of cell injury that occurs with
granulomatous inflammation in response to
certain microorganisms (tuberculosis). The host
response to the organisms is a chronic
inflammatory response and in the center of
the caseating granuloma there is an area of
cellular debris with the appearance and
consistency of cottage cheese.
 Fat Necrosis
When lipases are released into adipose tissue,
triglycerides are cleaved into fatty acids,
which bind and precipitate calcium ions,
forming insoluble salts.

These salts look chalky white on gross

examination and are basophilic in histological
sections stained with H&E.
FAT NECROSIS
 Fibrinoid Necrosis

The pattern of cell injury that occurs in

the wall of arteries in cases of vasculitis.
There is necrosis of smooth muscle cells of
the tunica media and endothelial damage
which allows plasma proteins, (primarily
fibrin) to be deposited in the area of
medial necrosis.
FIBRINOID NECROSIS
 Mechanisms of Cell Injury

• Cellular response to injury depends on nature,

duration and severity of injury.
• Consequences of injury depend on type, state
and adaptability of the injured cell.
• Cell injury results from different biochemical
mechanisms acting on essential cellular
components.
 Mechanisms of Cell Injury

• Depletion of ATP
• Mitochondrial Damage
• Entry of Calcium into the cell
• Increase reactive oxygen species (ROS)
• Membrane Damage
• DNA damage, Protein misfolding
 Depletion of ATP
ATP depletion and decreased ATP synthesis are
common with both hypoxic and toxic (or
chemical) injury, causing:
– Reduction in Na+, K+- ATPase pump activity
– Increase in anaerobic glycolysis (if possible)
– Failure of Ca++ export pump
– Reduced protein synthesis
 Consequences of
Mitochondrial
Damage
NECROSIS
Loss of membrane potential via
membrane permeability transition.
Results in failed oxidative
phosphorylation and loss of ATP.

OR

APOPTOSIS
Membrane damage leads to leakage
of Cytochrome c and other pro-
apoptotic proteins.
 Calcium Influx
• Intracellular Ca++ is normally low
and is sequestered in
mitochondria and endoplasmic
reticulum
• Extracellular Ca++ is high
• Gradients are normally
maintained by Ca++ Mg++ ATPase
pumps
• Increased cytosolic Ca++
activates enzymes such as
ATPases, phopholipases,
proteases, endonucleases that
can lead to cell injury and
death.
• Increased Ca++ is also pro-
apoptotic
 Reactive Oxygen Species

• Free radical is unpaired electron which makes the atom

or molecule extremely reactive.
• React with and modify cellular constituents.
• Initiate self perpetuating processes when they react
with atoms and molecules.
• Electrons are frequently added to O2 to create
biologically important ROS.
 Biologically Important ROS
• Superoxide anion radical O2 + e- --> O2-
– Produced by phagocyte oxidase, damages lipids, proteins and DNA.
• Hydrogen peroxide H2O2
– Generated by SOD and by oxidases, destroys microbes, may act at distant sites
(not a radical, per se, but very reactive).
• Hydroxyl radical .OH
– Generated from H2O by hydrolysis, most reactive, damages lipids,
proteins and DNA.
Reactive Oxygen Species

“NORMAL” ROS FUNCTIONS:

• Normal metabolism and
respiration
• Absorption of radiant energy
• Inflammation
• Enzymatic metabolism of
chemicals or drugs
• Nitric oxide synthesis
 Membrane Damage
• ROS  lipid peroxidation
• ↓ phospholipid synthesis
• ↑ phospholipid degradation (Ca influx activates phospholipases)
• Cytoskeletal damage (Ca influx also activates proteases)

EFFECTS:

Mitochondrial membrane damage

causes increased cytosolic Ca++,
oxidative stress, lipid peroxidation,
phospholipase activity, loss of
membrane potential, leakage of
Cytochrome c

Plasma membrane damage causes

loss of osmotic balance, loss of
proteins, enzymes and nucleic acids.

Injury to lysosome membranes causes

leakage of enzymes with destruction
of cellular components.
 DNA damage
Protein misfolding

• If DNA damage to cell is too severe, apoptosis

is initiated.
• Improperly folded proteins can also initiate
apoptosis (to be discussed shortly...)
 Several mechanisms of injury may be at
play in any given situation
Types of cell injury: Mechanisms of cell injury:
Ischemic and Hypoxic Injury • Depletion of ATP
(shutting off blood flow or • Mitochondrial Damage
deprivation of oxygen)
• Entry of Calcium into the
cell
Ischemia-Reperfusion Injury • Increase reactive oxygen
species (ROS)
Chemical Injury • Membrane Damage
• DNA damage, Protein
misfolding
Radiation injury
Regardless of the type or mechanism, extensive cell
injury results in death
either by necrosis or apoptosis
Necrosis
Loss of functional tissue
Impaired organ function, transient or permanent

Apoptosis
Removal of damaged or unnecessary cells
 General Characteristics

NECROSIS APOPTOSIS
“Accidental” “Programmed”

Usually affects large areas of Usually affects scattered individual

contiguous cells cells

Cells and organelles swell Cells contract

Control of intracellular environment is Control of intracellular environment

lost, cells rupture and spill contents maintained, cytoplasm packaged as
“apoptotic bodies”

INDUCES INFLAMMATION DOES NOT INDUCE INFLAMMATION

Apoptosis
 Apoptosis
• Mitochondrial (intrinsic) induction –activation of pro-apoptotic proteins and/or downregulation of
anti-apoptotic proteins leads to loss of mitochondrial membrane integrity and release of CytC and other
pro-apoptotic factors
• Death receptor (extrinsic) induction –cell receptors respond to signals (either secreted or by direct
contact with other cells) to directly induce apoptosis
• Convergent “execution” phase –caspases (cysteine-aspartic-acid-proteases) activate DNAses,
cytoskeletal proteases, and phosphatidylserine “flippase”
• Removal of dead cells –ligands expressed on surface membrane (e.g. phosphatidylserine and/or
glycoproteins) signal phagocytosis by macrophages
 Causes of Apoptosis may be Physiologic or
Pathologic

Physiologic Pathologic
• Embryogenesis and fetal • DNA damage due to radiation,
development. chemotherapy.
• Hormone dependent involution. • Accumulation of misfolded
Prostate glandular epithelium after
castration proteins leads to ER stress which
Regression of lactating breast after weaning ends with apoptosis.
• Cell loss in proliferating cell
populations. • Cell death in viral infections that
Immature lymphocytes induce apoptosis such as HIV and
Epithelial cells in the GI tract Adenovirus or by the host
• Elimination of self-reactive immune response such as
lymphocytes. hepatitis.
• Death of cells that have served their
function. • Organ atrophy after duct
Neutrophils, Lymphocytes obstruction.
 Intracellular accumulations
• Lipids
• Steatosis
• Cholesterol and Cholesterol Esters
• Proteins
• Glycogen
• Pigments
• Abnormal metabolism –
Steatosis (Fatty change)

• Abnormal protein folding

– Alpha 1 antitrypsin
deficiency

• Lack of enzyme –
Lysosomal storage
disease

• Indigestible material –
Carbon or heme
 Causes of Steatosis (Fatty Liver )
• Alcohol is a hepatotoxin that leads to increased
synthesis and reduced breakdown of lipids.
• Nonalcoholic fatty liver disease is associated with
diabetes and obesity.
• CCl4 and protein malnutrition cause reduced
synthesis of apoproteins.
• Hypoxia inhibits fatty acid oxidation.
• Starvation increases mobilization of fatty acids from
peripheral stores.
85-Fatty Liver (Gross)
85.1.pg.fattyliver
Intracellular lipid accumulation:
atherosclerotic plaque
 Intracellular lipid
accumulation: xanthoma
 Indigestible material: Pigments

 Exogenous Pigment – Carbon in lung = anthracosis

 Endogenous Pigments
Hemosiderin- multiple transfusions
Lipofuscin- aging pigment
Melanin- skin and neurotransmission
Bilirubin-hepatocytes
Exogenous pigment
Anthracotic pigment in Lung
Endogenous pigments
Hemosiderin
• Brown pigment
• Breakdown product of
hemoglobin
• Contains ferrous iron (so
turns blue when stained
with K-ferrocyanide, aka
Prussian blue stain)

Lipofuscin
• Brown pigment
• “wear and tear” pigment
from peroxidation of
membrane lipids
• Does NOT contain ferrous
iron (so does not react
with Prussian blue stain)
• Present in long-lived cells
 Pathologic Calcification
• Dystrophic Calcification – occurs in areas of necrosis
and atherosclerosis.

• Metastatic Calcification – occurs in normal tissues

when there is hypercalcemia.
 Metastatic Calcification
• Excess Parathyroid hormone
• Destruction of bone
• Vitamin D disorders
• Renal failure
 Conclusions
• Cell injury may occur by a variety of mechanisms and sources -
endogenous (ischemia/inflammation) or exogenous (drugs/toxins)
• Cell injury can be reversible or irreversible.
• Reversible cell injury can result in changes which may recover when the
cause is removed, or which may persist.
• Irreversible (lethal) cell injury may cause only transient functional
impairment if the dead cells can be replaced.
• Alternatively, lethal cell injury may lead to permanent functional
impairment if the dead cells can not be replaced.
• Cell death (apoptosis) is a normal mechanism to remove damaged cells
which can be activated in pathologic conditions.
• Substances may be deposited within cells in response to cell injury.
Inflammation and
Wound Healing
 What is Inflammation?
• Response to injury (including infection)
• Reaction of blood vessels leads to:
– Accumulation of fluid and leukocytes in extravascular tissues
• Destroys, dilutes, or walls off the injurious agent
• Initiates the repair process
• Fundamentally a protective response
• May be potentially harmful
– Hypersensitivity reactions to insect bites, drugs, contrast media in radiology
– Chronic diseases: arthritis, atherosclerosis
– Disfiguring scars, visceral adhesions
• Consists of two general components
– Vascular reaction
– Cellular reaction
• Controlled by a variety of chemical mediators
– Derived from plasma proteins
– Derived from cells inside and outside of
blood vessels
 Historical Highlights
• Celsus, a first century A.D. Roman, listed four
cardinal signs of acute inflammation:
– Rubor (erythema [redness]): vasodilatation,
increased blood flow
– Tumor (swelling): extravascular accumulation of
fluid
– Calor (heat): vasodilatation, increased blood flow
– Dolor (pain)
 Types of Inflammation
• Acute inflammation • Chronic inflammation
– Short duration – Longer duration
– Edema – Lymphocytes & macrophages
– Mainly neutrophils predominate
– Fibrosis
• Granulomatous – New blood vessels
inflammation (angiogenesis)
– Distinctive pattern of chronic
inflammation
– Activated macrophages
(epithelioid cells)
predominate
– +/- Multinucleated giant cells
 Acute Inflammation
• Three major components:
– Increase in blood flow (redness & warmth)
– Edema results from increased hydrostatic
pressure (vasodilation) and lowered
intravascular osmotic pressure (protein leakage)
– Leukocytes emigrate from microcirculation and
accumulate in the focus of injury
• Stimuli: infections, trauma, physical or
chemical agents, foreign bodies, immune
reactions
Edema in inflammation
Edema is a general term for
swelling (usu. due to fluid)

Plasma proteins in blood maintain

a “colloid osmotic pressure” to
help draw fluid that leaks out
into tissue bed via hydrostatic
pressure

Dysregulation of hydrostatic
pressure (e.g. heart failure)
and/or colloid pressure
(decresased protein
synthesis/retention) pushes out
more fluid (transudate) into
tissue bed

Inflammation causes endothelial

cells to separate, thus allowing
fluid + protein (exudate) to
enter tissue bed.
 Leukocyte Extravasation
• Extravasation: delivery of leukocytes from the vessel lumen to the interstitium
– In the lumen: margination, rolling, and adhesion
– Migration across the endothelium (diapedesis)
– Migration in the interstitial tissue (chemotaxis)
• Leukocytes ingest offending agents (phagocytosis), kill microbes, and degrade necrotic
tissue and foreign antigens
• There is a balance between the helpful and harmful effects of extravasated leukocytes
Neutrophil Morphology

Eosinophil
Neutrophils
Leukocyte Margination

Photomicrograph courtesy of Dr. James G. Lewis

Leukocyte Diapedesis

Photomicrograph courtesy of Dr. James G. Lewis

Sequence of Leukocyte Emigration

• Neutrophils predominate during the

first 6 to 24 hours
• Monocytes in 24 to 48 hours
• Induction/activation of different
adhesion molecule pairs and specific
chemotactic factors in different phases of
inflammation
Sequence of Events - Injury
Sequence of Events - Infection
Outcomes of Acute Inflammation
• Complete resolution
• Abscess formation
• Fibrosis
– After substantial tissue destruction
– In tissues that do not regenerate
– After abundant fibrin exudation, especially
in serous cavities (pleura, peritoneum)
• Progression to chronic inflammation
 Types of Inflammation: acute vs. chronic
Types of repair: resolution vs. organization (fibrosis)
Morphologic Patterns of Acute Inflammation
• Serous inflammation: Outpouring of thin fluid
(serous effusion, blisters)
• Fibrinous inflammation: Body cavities; leakage of
fibrin; may lead to scar tissue (adhesions)
• Suppurative (purulent) inflammation: Pus or
purulent exudate (neutrophils, debris, edema
fluid); abscess: localized collections of pus
• Ulcers: Local defect of the surface of an organ or
tissue produced by the sloughing (shedding) of
inflammatory necrotic tissue
Fibrinous Pericarditis
Fibrinous Pericarditis
Fibrinous Pleuritis
Suppurative (purulent) inflammation:
Abscess
Gastric Ulcer
Gastric Ulcer
 Systemic Manifestations
• Endocrine and metabolic
– Secretion of acute phase proteins by the liver
– Increased production of glucocorticoids
(stress response)
– Decreased secretion of vasopressin leads to
reduced volume of body fluid to be warmed
• Fever
– Improves efficiency of leukocyte killing
– Impairs replication of many offending organisms
 Systemic Manifestations
• Autonomic
– Redirection of blood flow from skin to deep
vascular beds minimizes heat loss
– Increased pulse and blood pressure
• Behavioral
– Shivering (rigors), chills (search for warmth),
anorexia (loss of appetite), somnolence, and
malaise
 Systemic Manifestations

• Leukocytosis: increased leukocyte count in the

blood
– Neutrophilia: bacterial infections
– Lymphocytosis: infectious mononucleosis, mumps,
measles
– Eosinophilia: Parasites, asthma, hay fever
• Leukopenia: reduced leukocyte count
– Typhoid fever, some viruses, rickettsiae, protozoa
 Chronic Inflammation
• Inflammation of prolonged duration (weeks or
months)
– Active inflammation, tissue destruction, and
attempts at repair are proceeding simultaneously
• May follow acute inflammation or begin
insidiously and often asymptomatically
– Persistent infections, exposure to toxic agents
such as silica (silicosis), or by autoimmunity
 Chronic Inflammation
• Persistent infections
– Treponema pallidum [syphilis], viruses, fungi, parasites
• Exposure to toxic agents
– Exogenous: silica (silicosis)
– Endogenous: toxic plasma lipid components
(atherosclerosis)
• Autoimmunity
– Rheumatoid arthritis, systemic lupus erythematosus
 Chronic Inflammation

• Histological features
– Infiltration with mononuclear cells
(macrophages, lymphocytes, and plasma cells)
– Tissue destruction
(induced by the inflammatory cells)
– Healing by replacement of damaged tissue by
connective tissue (fibrosis)
and new blood vessels (angiogenesis)
Chronic Inflammatory Cells

Lymphocytes

Macrophages
Chronic Inflammation
Chronic Inflammation
 Macrophages
• Monocytes begin to
emigrate into tissues early
in inflammation where
they transform into the
larger phagocytic cell
known as the macrophage
• Macrophages
predominate by 48 hours
– Recruitment (circulating
monocytes); division;
immobilization
• Activation results in
secretion of biologically
active products
Macrophages
Other Cells in Chronic Inflammation

• Lymphocytes
– Produce inflammatory mediators
– Participate in cell-mediated immune reactions
– Plasma cells produce antibody
– Lymphocytes and macrophages interact in a
bi-directional fashion
Chronic Inflammatory Cells

Plasma cells Russell bodies

Other Cells in Chronic Inflammation

• Eosinophils
– Immune reactions mediated by IgE
– Parasitic infections
• Eosinophil granules contain a protein that is
toxic to parasites
• Mast cells
– Release mediators (histamine) and cytokines
Eosinophil Morphology
Chronic Cellulitis
 Granulomatous Inflammation

• Distinctive pattern of chronic inflammation

– Predominant cell type is an activated macrophage
with a modified epithelial-like (epithelioid)
appearance
– Giant cells may or may not be present
• Granuloma:
Focal area of granulomatous inflammation
 Granulomatous Inflammation

• Foreign body granulomas:

Form when foreign material is too large to
be engulfed by a single macrophage
• Immune granulomas:
Insoluble or poorly soluble particles elicit
a cell-mediated immune response
Granulomatous Response to Suture
Chemical Mediators of Inflammation
• General principles of chemical mediators
– May be derived from plasma or cells
– Most bind to specific receptors on target cells
– Can stimulate release of mediators by target cells, which may amplify or ameliorate the
inflammatory response
– May act on one or a few target cells, have widespread targets, and may have differing effects
depending on cell and tissue types
– Usually short-lived
– Most have the potential to cause harmful effects
 Chemical Mediators of Inflammation
• Vasoactive mediators • Chemotactic factors
– Histamine – Complement (C5a)
– Bradykinin – Leukotriene (B4)
– Complement (C3a, C5a) – Platelet activating factor
– Prostaglandins/leukotrienes – Cytokines (IL-1, TNF)
– Platelet activating factor – Chemokines
– Nitric oxide – Nitric oxide
 Histamine
• Mast cells (also basophils and platelets)
• Release mechanisms
– Binding of antigen (allergen) to IgE on
mast cells releases histamine-
containing granules
– Release by nonimmune mechanisms
such as cold, trauma, or other
chemical mediators
– Release by other mediators
• Dilates arterioles and increases
permeability of venules (wheal and flare
reaction)
 Complement
• Proteins found in greatest concentration in
the plasma
• Require activation
• Increase vascular permeability and cause
vasodilation
– Mainly by releasing histamine from mast cells
• Increase leukocyte adhesion, chemotaxis, and
activation
• C3b attaches to bacterial wall and enhances
phagocytosis by neutrophils & macrophages
 Bradykinin

• Small peptide released from plasma

precursors
• Increases vascular permeability
• Dilates blood vessels
• Causes pain
• Rapid inactivation
 Arachidonic Acid Metabolites
• Prostaglandins
– Vasodilators: prostacyclin (PGI2), PGE1, PGE2, PGD2
– Vasoconstrictors: thromboxane A2
– Pain (PGE2 makes tissue hypersensitive to bradykinin)
– Fever (PGE2)
– Production blocked by steroids and nonsteroidal anti-
inflammatory agents (NSAIDs)
• Leukotrienes
– Increase vascular permeability: leukotrienes C4, D4, E4
– Vasoconstriction: leukotrienes C4, D4, E4
– Leukocyte adhesion & chemotaxis: leukotriene B4,
HETE, lipoxins
– Production blocked by steroids but not conventional
NSAIDs
Figure 2-16 Robbins and Cotran Pathologic Basis of Disease, 7th
Ed.
 Platelet Activating Factor
• Subclass of phospholipids
• Synthesized by stimulated platelets,
leukocytes, endothelium
• Inflammatory effects
– Stimulates platelet aggregation
– Vasoconstriction and bronchoconstriction
– Vasodilation and increased venular permeability
– Increased leukocyte adhesion to endothelium,
chemotaxis, degranulation, and oxidative burst
– Increases synthesis of arachidonic acid
metabolites by leukocytes and other cells
 Cytokines
• Proteins produced by many cell types
(principally activated lymphocytes &
macrophages)
• Modulate the function of other cell types
• Interleukin-1 (IL-1) and tumor necrosis factor
(TNF) are the major cytokines that mediate
inflammation
Figure 2-18 Robbins and Cotran Pathologic Basis of Disease, 7th
Ed.
 Chemokines
• Small proteins that act primarily as
chemoattractants for specific types of
leukocytes (approximately 40 known)
• Stimulate leukocyte recruitment in
inflammation
• Control the normal migration of cells through
tissues (organogenesis and maintenance of
tissue organization)
• Examples: IL-8, eotaxin, lymphotactin
 Nitric Oxide

Figure 2-19 Robbins and Cotran Pathologic Basis of Disease, 7th

Ed.
 Other Mediators
• Neutrophil granules:
– Cationic proteins increase vascular permeability,
immobilize neutrophils, chemotactic for
mononuclear phagocytes
– Neutral proteases generate other mediators and
degrade tissue
• Oxygen-Derived Free Radicals:
– Produced during phagocytosis by neutrophils
(“respiratory burst”)
– Tissue damage including endothelium
Summary of Inflammatory Mediators

• Vasodilation • Increased vascular

– Prostaglandins permeability
– Nitric oxide – Histamine, serotonin
– Histamine
– Complement (C3a, C5a)
– Bradykinin
– Leukotrienes (C4, D4, E4)
– Platelet Activating Factor
– Substance P
Summary of Inflammatory Mediators

• Chemotaxis, • Fever
leukocyte activation – Interleukin-1
– Complement (C5a) – Tumor necrosis factor
– Leukotriene B4 – Prostaglandins
– Chemokines
– IL-1, TNF
– Bacterial products
 Summary of Inflammatory Mediators

• Pain • Tissue Damage

– Prostaglandins – Neutrophil and
– Bradykinin macrophage lysosomal
enzymes
– Oxygen metabolites
– Nitric oxide
 Wound Healing
• A complex but orderly process involving many of the
chemical mediators previously discussed, along with
many other growth factors and cell-matrix interactions.

• Occurs in the following steps:

1. Injury induces acute inflammation
2. Parenchymal cells regenerate
3. Both parenchymal and connective tissue cells migrate and
proliferate
4. Extracellular matrix is produced
5. Parenchyma and connective tissue matrix remodel
6. Increase in wound strength due to collagen deposition
Wound Healing Time Course
 Granulation Tissue

• Hallmark of healing
• Term comes from soft, pink, granular
appearance when viewed from the surface of
a wound
• Histology: Proliferation of small blood vessels
and fibroblasts; tissue often edematous
Granulation Tissue
Granulation Tissue
Healing by 1st intention vs. 2nd intention

By 1st intention:
• “clean” incision
• limited scarring or
wound contraction

By 2nd intention:
• ulcers or
lacerations
• often scarring and
wound contraction
Ulcers: an example of healing by 2nd intention
Resolution of Inflammation:
“Regeneration” vs. “Healing”
An example of healing by fibrosis:
Myocardial Infarction

Edge of acute infarct

Myocardial Infarct: healing (aka “remote”)

Healing (remote) infarct

Myocardial Infarct: healing (trichrome stain)

Masson trichrome stain for collagen

 Variables affecting repair
• Infection –prolongs inflammation, increases degree of tissue injury
• Nutrition –protein or vitamin deficiency can impair synthesis of new proteins
• Anti-inflammatory drugs –can impede fibrosis necessary for repair
• Mechanical variables –tension, pressure, or the presence of foreign bodies can affect repair
• Vascular disease –limits nutrient and oxygen supply required for repairing tissues
• Tissue type –only tissues capable of renewing will regenerate, otherwise healing is by fibrosis
• Degree of exudate removal –adequate removal of exudate allows RESOLUTION of the injury
(general restoration of the normal tissue architecture); inadequate removal results in ORGANIZATION
(abnormal, dysfunctional tissue architecture)
• Regulation of cell proliferation –abnormal proliferation of connective tissue may inhibit re-
epithelialization and/or raised scars (keloids)