Causes of cell injury

Mechanism of cell injury

FAIZA ARIF
 Cell Injury

• Cell injury is reversible up to a certain point.

• “Any change that results in a loss of the ability to maintain normal or

adapted homeostatic state”

• Cell death, is the ultimate result of cell injury

 Causes of Cell Injury

1) Oxygen Deprivation (Hypoxia). It is a common cause of cell injury and cell

death.

-Hypoxia can be due to :

A- inadequate oxygenation of the blood.

B- loss of the oxygen-carrying capacity of the blood, as in anemia or carbon

monoxide poisoning.

• Depending on the severity of the hypoxic state, cells may adapt, undergo
injury, or
die.
 cont
2…) Physical Agents :

- Mechanical trauma,

- Burns,

- Deep cold,

- Sudden changes in atmospheric pressure,

- radiation, and electric shock,

cont
…
3) Chemical Agents and Drugs

- oxygen, in high concentrations

- poisons, such as arsenic, cyanide, or mercuric salts

- environmental and air pollutants

- insecticides, herbicides, industrial and occupational hazards

- alcohol and narcotic drugs and therapeutic drugs

 cont
…
4) Infectious Agents e.g. bacteria, fungi, viruses and parasites.

5) Immunologic Reactions.

6) Genetic Derangements.

7) Nutritional Imbalances
 4 weak points of the cell

Cell membrane integrity, critical to cellular ionic and osmotic

homeostasis

ATP synthesis, largely via mitochondrial aerobic respiration

Protein synthesis (RER)

Integrity of the genetic apparatus (nucleus)

Mechanisms of Cell Injury
Two models
a. Ischemic injury
b. Chemical injury
 Ischemi vs Hypoxia
a supply
 Loss of blood  Lack of Oxygen in tissues

 (↓ed O2 as well as ↓ed delivery of  Maybe due to ischemia or due to other

other nutrients . causes like due to less RBCs in the

 ↓ed removal of toxic waste products of blood, or less Oxygen in the atmosphere

the cells so there is accumulation of etc.

toxic substances, e.g., Lactic acid.  Less severe injury than with Ischemia
 Quicker and More severe injury than

with just lack of Oxygen.

 MECHANISM OF CELL
INJURY
1. Depletion of ATP.

2. Mitochondrial Damage.

3. Influx of intracellular calcium & loss of calcium homeostasis.

4.Accumulation of oxygen-derived free radicals (oxidative stress).

5. Defects In Membrane Permeability
 1. DEPLETION OF ATP

 ATP is required for many synthetic and degradative processes within the cell

 ATP depletion and decreased ATP synthesis are associated with both hypoxic
and chemical (toxic) injury.
 Effects of depleted ATP
 The activity of the plasma membrane energy-dependent sodium pump is
reduced. It causes sodium to accumulate intracellular and potassium to diffuse
out of the cell causing cell swelling.

 In ischemia (reduce O2 supply), oxidative phosphorylation ceases and cells rely

on anaerobic glycolysis for energy resulting in quick depletion of glycogen stores.

 Glycolysis results in the accumulation of lactic acid which reduces the

intracellular pH, resulting in decreased activity of many cellular enzymes.
 Failure of the Ca2+ pump leads to influx of Ca2+, with damaging effects
on numerous cellular components.

 Ribosome's detach from the RER and polysomes breakdown into

monosomes, leading to reduction in protein synthesis.

 Ultimately, irreversible damage to mitochondrial and lysosomal membranes

occurs, and cell undergoes necrosis.

 In cells deprived of oxygen or glucose, proteins may become misfolded,

and trigger the misfolded protein response leading to cell injury and even
death.
2. Mitochondrial Damage
 Mitochondria are important targets for all types of injury, including hypoxia and

toxins.

Mitochondria can be damaged by :

A- Increases of cytosolic Ca2+

B- Oxidative stress

C- Breakdown of
phospholipids,
 Mitochondrial damage results, mitochondrial permeability transition, present in
the inner mitochondrial membrane.

 In the initial phase it is reversible but once mitochondrial permeability transition

is irreversible it becomes a death.

 Mitochondrial damage can also be associated with leakage of cytochrome-C into

the cytosol.
Seen just
before cell
death
 3.Influx of intracellular calcium & loss of calcium
homeostasis.

Ischemia causes an increase in cytosolic calcium concentration. Increased Ca2+

in turn activates a number of enzymes, e.g.

- ATPases ( ATP depletion),

-Phospholipases (which cause membrane damage),

- Proteases (which break down both membrane and cytoskeleton proteins), and

-Endonucleases (which are responsible for DNA and chromatin fragmentation).

Effects of excess
calcium in the cytosol

Cut-off point
between
reversible cell
injury
and cell
death??
 4. Accumulation of oxygen-derived free radicals
(oxidative stress)
Free radicals are chemical species that have unpaired electrons in an outer orbit.

 They are initiated within cells in several ways:

a) Absorption of radiant energy (e.g., ultraviolet light, x-rays).

b) Enzymatic metabolism of exogenous chemicals or drugs.

c)The reduction-oxidation reactions that occur during normal metabolic processes

normal produce small amounts of toxic intermediates, these include superoxide
anion radical (O2-), hydrogen peroxide (H2O2), and hydroxyl ions (OH).
d) Transition metals such as iron and copper.

e) Nitric Oxide (NO), an important chemical mediator generated by various

cells, can act as a free radical.

 Effects of these reactive species are

• Lipid peroxidation of membranes: result in extensive membrane, organelle, and

cellular damage.

• Oxidative modification of proteins. resulting in protein fragmentation.

• Lesions in DNA. This DNA damage has been implicated in cell aging and
malignant transformation of cells.
Mechanism of chemical injury:

Most chemicals do not produce cell

injury directly by themselves, but once
they are metabolized in the body, the
metabolites are the injurious agent:
Example is Carbon tetrachloride
poisoning
 Membrane
Damage
• Lipid peroxidation
• Free Radicals
• F.R. Chemical has unpaired electron in 0uter
orbit -- oxidation reduction
reactions

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 Membrane Damage

• Free Radicals
• can react with
• Organic and
• Inorganic substances
• Proteins
• Lipids
• Nucleoproteins

Making them useless or

unstable
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 Membrane Damage

• Free Radicals
• Once this reaction is started – it
continues…

●●●
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 Mixed function Oxidases ●
CCl4 ●
CCl3 + Cl
Cytochrome P450

CCl + Cl + Lipids
● ● Lipid
ra dical
3

Lipid Radical L+ipOi2d radical Lipid peroxyl

radical +
Lipid peroxide
Lipid peroxide -- highly unstable --
break down

aldehydes 29
• Free Radicals
• Also degrade enzymes
• Fragmentation of polypeptide chains
• Cross-linking sulfhydryl (-SH) groups
• DNA
• Strands break
• Abnormal cross linking

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• Lipid peroxidation
• Main attack is membrane (especially
of organelles)
• Cu and Fe -- catalyst
• Mitochondria -- cytochromes
• ER
Lysosomal membranes – slightly resistant

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 SOURCES
OF
FREE
RADICALS
33
 Superoxide Anion Radical

Superoxide anion radical

Incomplete O2 Reduction in Phagocyte

O2 •O2-
+1e–
Oxidative phosphorylation ATP
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 Hydrogen Peroxide
• In peroxisomes formation of Hydrogen peroxide (H2O2)
Hydrogen peroxide (H2O2) can be formed upon two-electron reduction of
molecular oxygen or one-electron reduction of superoxide anion (O .–):2

Two-electron reduction of molecular oxygen

35
• In peroxisomes formation of Hydrogen peroxide (H2O2)
Hydrogen peroxide (H2O2) can be formed upon two-electron reduction of
molecular oxygen or one-electron reduction of superoxide anion (O .–):
2

One-electron reduction of superoxide anion

36
 Hydroxyl Radical
• Hydroxyl radical (HO●) is the most reactive oxygen species originating from
a reaction between superoxide anion radical (O2 ●–) and hydrogen peroxide
(H2O2)

37
 Other source: during excessive exposure to ionizing radiation,
originates from the breakdown of hydrogen peroxide (H2O2) via
a Fenton reaction.

• The Fenton reaction entails a metal-dependent reduction of

hydrogen peroxide (H2O2) to hydroxyl radical (HO● ).
• Transition metals, such as copper (Cu), iron (Fe), and cobalt
(Co), in their reduced form catalyze this reaction

38
• NO is a widespread chemical mediator of
inflammation
• Can act as a free radical
• Can be converted into peroxynitrite

• Ionizing radiation (UV light, X-rays)

• H2O hydrolyzed into •OH and •H (hydrogen) free radicals.

• Breakdown of exogenous chemicals (CCl4).

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 FREE RADICAL
CONVERSTION TO
NON-RADICAL
SPECIES / PRODUCTS
 REMOVAL OF SUPEROXIDE ANION

SOD based conversation is 10,000 fold faster

 REMOVAL OF HYDROGEN PEROXIDE

Catalase

Glutathione
peroxidase

• Catalase. This enzyme is located in the peroxisomes

• Glutathione Peroxidase. The enzyme occurs in cytosol and
the mitochondrial matrix
 REMOVAL OF HYDROXYL RADICAL

Glutathione peroxidase
2OH● + 2GSH 2H 2O + GSSH
(Oxidized)

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 REMOVAL OF PEROXYL RADICAL BY
VITAMIN E

ROO● + TocOH ROOH + TocO●

Peroxyl Vitamin E Hydroperoxide Oxidized
radical tocopherol radical

ROO●+ TocO● ROOH Hydroperoxide

Peroxyl Oxidized +
radical
( non-radical product)
tocopherol radica l

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Vitamin C

ascorbic acid ascorbyl radical

45