DR. ROOPAM JAIN PROFESSOR & HEAD OF DEPT. DEPT. OF PATHOLOGY & BLOOD BANK

1. Cell Injury
DR. ROOPAM JAIN
PROFESSOR & HEAD, PATHOLOGY

2. PATHOGENESIS OF
CELL INJURY

3. common scheme applies to most forms of cell injury by
various agents:
• 1. Factors pertaining to etiologic agent and host
• 2. Common underlying mechanisms
• 3. Usual morphologic changes
• 4. Functional implications and disease outcome

4. PATHOGENESIS OF ISCHAEMIC &
HYPOXIC INJURY

6. REVERSIBLE CELL INJURY
• 1. Decreased generation of cellular ATP: Damage by
ischaemia from interruption versus hypoxia from other
causes
• 2. Intracellular lactic acidosis: Nuclear clumping
• 3. Damage to plasma membrane pumps: Hydropic
swelling and other membrane changes
• 4. Reduced protein synthesis: Dispersed ribosomes

7. IRREVERSIBLE CELL INJURY
• Two essential phenomena always distinguish irreversible
from rever sible cell injury
• Inability of the cell to reverse mitochondrial
dysfunction on reperfusion or reoxygenation.
• Disturbance in cell membrane function in general, and
in plasma membrane in particular

8. IRREVERSIBLE CELL INJURY
• 1. Calcium influx: Mitochondrial damage
• 2. Activated phospholipases: Membrane damage
• 3. Intracellular proteases: Cytoskeletal damage
• 4. Activated endonucleases: Nuclear damage
• 5. Lysosomal hydrolytic enzymes: Lysosomal damage,
cell death and phagocytosis

9. Ultrastructural changes during cell injury
due to hypoxia-ischaemia.

10. Ultrastructural changes during cell injury
due to hypoxia-ischaemia.

11. Ultrastructural changes during cell injury
due to hypoxia-ischaemia.

13. IRREVERSIBLE CELL INJURY
• Persistence of ischaemia or hypoxia results in irreversible damage
to the structure and function of the cell (cell death).
• Two essential phenomena always distinguish irreversible from
reversible cell injury (Fig. 2.2):
• Inability of the cell to reverse mitochondrial dysfunction on
reperfusion or reoxygenation.
• Disturbance in cell membrane function in general, and in plasma
membrane in particular.

14. • In addition, there is further reduction in ATP, continued
depletion of proteins, reduced intracellular pH, and
leakage of lysosomal enzymes into the plasma. These
biochemical changes have effects on the ultrastructural
components of the cell (Fig. 2.3, B):

15. • 1. Calcium influx: Mitochondrial damage
• 2. Activated phospholipases: Membrane damage
• 3. Intracellular proteases: Cytoskeletal damage
• 4. Activated endonucleases: Nuclear damage
• 5. Lysosomal hydrolytic enzymes: Lysosomal
damage, cell death and phagocytosis

16. Ischaemia-Reperfusion
Injury and Free Radical-
Mediated Cell Injury
• Depending upon the duration of ischaemia/hypoxia,
restoration of blood flow may result in the following 3
different consequences:
• 1. From ischaemia to reversible injury
• 2. From ischaemia to irreversible injury
• 3. From ischaemia to reperfusion injury

17. • Ischaemia-reperfusion injury occurs due to excessive
accumulation of free radicals or reactive oxygen species.
The mechanism of reperfusion injury by free radicals is
complex but following three aspects are involved:
• 1. Calcium overload.
• 2. Excessive generation of free radicals (superoxide,
H2O2, hydroxyl radical, pernitrite).
• 3. Subsequent inflammatory reaction.

18. Oxygen free radical generation
• i) Superoxide oxygen (O’2): one electron
• ii) Hydrogen peroxide (H2O2): two electrons
• iii) Hydroxyl radical (OH– ): three electrons

20. Other free radicals
• i) Nitric oxide (NO) and peroxynitrite (ONOO)
• ii) Halide reagent (chlorine or chloride)
• iii) Exogenous sources

21. Cytotoxicity of free radicals
• Free radicals may produce membrane damage
by the following mechanisms
• i) Lipid peroxidation
• ii) Oxidation of proteins
• iii) DNA damage
• iv) Cytoskeletal damage

23. Conditions with free radical injury Currently,
oxygenderived free radicals have been known to play
an important role in many forms of cell injury:
• i) Ischaemic reperfusion injury
• ii) Ionising radiation by causing radiolysis of water
• iii) Chemical toxicity
• iv) Chemical carcinogenesis
• v) Hyperoxia (toxicity due to oxygen therapy)
• vi) Cellular ageing
• vii) Killing of microbial agents
• viii) Inflammatory damage
• ix) Destruction of tumour cells
• x) Atherosclerosis

24. Stress Proteins in Cell Injury
• When cells are exposed to stress of any type, a
protective response by the cell is by release of
proteins that move molecules within the cell
cytoplasm; these are called stress protein.
• Th ere are 2 types of stress-related proteins:
• heat shock proteins (HSP) and
• ubiquitin (so named due to its universal
presence in the cells of the body)

25. PATHOGENESIS OF CHEMICAL INJURY
• Chemicals induce cell injury by one of the two
mechanisms:
• by direct cytotoxicity, or
• by conversion of chemical into reactive metabolites.

26. PATHOGENESIS OF PHYSICAL INJURY
• Killing of cells by ionising radiation is the result of
direct formation of hydroxyl radicals
• These hydroxyl radicals damage the cell membrane
as well as may interact with DNA of the target cell.

27. Mechanisms of cell injury by ionising radiation.