Cell injury occurs when stresses exceed a cell's adaptive capacity. Reversible injury involves loss of function but not death, while irreversible injury leads to cell death. The key mechanisms of injury include ATP depletion, oxidative stress from free radicals, loss of calcium homeostasis, and mitochondrial and genetic damage. Morphological changes range from swelling in reversible injury to lysosomal rupture and inflammation in irreversible injury and death.

1. Lect.no.3
Cell injury

2. hypertesion C
E
1. If the adaptive capacity
is exceeded L
Prolonged starvation
i.e.adaptation is no L
longer possible
Incomplete occlusion
of coronary artery
I
Complete sudden N
2. if the injury is rapid
i.e.No time for adaptation
occlusion J
U
3. When adaptation is not possible for any reason (neurons)
R
Y

3. When cells encounter physiological stresses or pathological stimuli, they
undergo adaptation, achieving a new a steady state and preserving viability.
adaptation
normal Irreversible Injury (cell death)
with severe and
persistent stress,
irreversible injury
results.
Reversible Injury
If adaptation is exceeded, cell injury occurs.
Within certain limits, injury is reversible.
If this limit exceeded, injury becomes irreversible leading to cell death.

4. Mechanisms of cell injury
General principles
• 1. The cellular response to injury depends
on the type, duration and severity of the
injury.

5. General principles
• 2.The consequences of an injurious stimulus
depend on the type, state, adaptability, and
genetic makeup of injured cell.
• Skeletal muscle accommodates complete
ischemia for 2 to 3 hours without irreversible
injury.
• cardiac muscle dies after 20 to 30 minutes.
• Neuron dies after a few minutes.

6. Injury starts at subcellular level

7. General principles
3. Cell injury results from an abnormality in one
or more essential cellular components: four
intracellular systems are particularly vulnerable.
• Cell membrane integrity, critical to
cellular ionic and osmotic homeostasis;
• ATP generation, largely via
mitochondrial aerobic respiration;
• Protein synthesis;
• Intergrity of the genetic apparatus.

8. Causes of Cell Injury
1. O2 deprivation which impairs aerobic respiration &
the ability to produce ATP. This is a common
cause of cell death.
a. Hypoxia- lack of O2 results in
decreased aerobic respiration
b. Ischemia- lack of O2 & metabolic
substrates
2. Physical agents- mechanical trauma, temperature
changes, shock, radiation etc.
3. Chemical agents - acids, bases, toxins,
therapeutic drugs, pollutants, etc.

9. Causes of Cell Injury
4. Infectious agents
5. Immunologic reactions
a. Hypersensetivity reactions
b. Immune deficiency.
c. Autoimmune reaction
6. Genetic derangements
7. Nutritional imbalances
a. Deficiencies
b. Excesses

10. Mechanisms & Pathogenesis of
Cell Injury
INJURY cause
• Defects in plasma membrane
permeability.
• ATP depletion
• Accumulation of Oxygen-Derived free
radical (Oxidative stress)
• Loss of calcium homeostasis.
• Mitochondrial damage.
• Genetic damage

11. REVERSIBLE CELL INJURY
• It occurs when environmental changes
exceed the capacity of the cell to maintain
normal hemostasis or adaptation. If the
stress is removed in tissue or if the cell
withstand the assult the injury is reversible

12.  ATP depletion <5-10% of normal
• ATP use > ATP synthesis is a common
consequence of both ischemic & toxic injury.
• ATP production occurs via 2 related mechanism
 Glycolysis – cytosolic, low yield, lactate
production (↓pH)
 Oxidative phosphorylation – mitochondrial, high
yield
• Hypoxia results in ↑ed glycolysis (depletion of
glycogen & ↓pH)
• ATP is critical for:
 Membrane transport
 Maintenance of ionic gradients ( Na+, K+ Ca2+)
 Protein synthesis
 Cytoskeletal function (microfilaments)

13. Mechanisms of Cell Injury
in ischemia/hypoxia.
Depletion of ATP
Na+
K+
Ca2+

14. Morphology of Reversible Cell
Injury
Reversible Injury
Cellular swelling
Fatty change

15. Ischemic injury

17. Reversible vs irreversible
cell injury
Reversible injury Irreversible injury
* Decreased ATP * Amorphous
levels densities in
mitochondria
* Ion imbalance
* Severe membrane
* Swelling
damage
 Decreased pH
* Lysosomal rupture
 Inflammation in
surrounding tissues

18. General principle
• Cellular function is far before cell death
occurs, and the morphologic changes of
cell injury(or death) lag far behind both.
• REVERSIBLE  Loss of function
• IRREVERSIBLE
• DEATH
• EM
• LIGHT MICROSCOPY
• GROSS APPEARANCES

19. Timing of biochemical & morphologic changes in cell injury

20. DEATH:
ELECTRON MICROSCOPY

21. DEATH:
LIGHT MICROSCOPY

22. DEATH: GROSS APPEARANCE

23. FREE RADICALS
• Molecular species with a single unpaired
electron available in an outer orbital shell.
Single free radicals initiate chain reactions
which destroy large numbers of organic
molecules

24. • The most important free radicals are
probably those derived from oxygen, i.e.,
superoxide (O.-2) and hydroxyl radical
(OH.); hydrogen peroxide, though not a
free radical, is two hydroxyl radicals
joined.

26. • Free radicals may be generated in the following ways:
• 1. By absorbing radiant energy (UV, x-rays; striking
water, these generate a hydrogen atom and a hydroxyl
radical.
• 2. As part of normal metabolism (for example, xanthine
oxidase and the P450 systems generate superoxide; our
white cells use free radicals to attack and kill invaders)
• 3. As part of the metabolism of drugs and poisons (the
most famous being CCl3.-, from carbon tetrachloride;
even O2 in high concentrations generates enough free
radicals to gravely injure the lungs).

27. Free Radicals
Free Radical Defense
1. Spontaneous decay
2. Antioxidants (enzymatic & non-
enzymatic)
3. Free radical scavenging systems

28. FREE-RADICAL EFFECTS
• 1. Oxidation of unsaturated fatty acids in
membranes ("lipid peroxidation", etc.).
• 2. Cross-linking of sulfhydryl groups of
proteins.( protein denaturation)
• 3.Genetic mutations (DNA depolymerization)