Cell injury

Yodit Getahun, MD
Cell injury
• Cell injury occurs when the cells cannot adapt to their new environment
• Causes :- hypoxia
ischemia
physical and chemical agents
trauma
infectious agents
radiation
toxins
metabolic abnormalities (acquired or genetic)
aging , nutritional imbalances
immune dysfunction (hypersensentivity rxns, autoimmune diseases
Cont’d
• Hypoxia and ischemia are two common sources of cellular injury
• ischemia is much more damaging because it involves hypoxia plus a
lack of other nutrients and an accumulation of toxic cellular
metabolites
• Cell injury varies from cell to cell. It depends upon the type, duration,
& severity of injury and the type, adaptability, and makeup of the
affected cell.
Cont’d
• Four cellular systems are especially vulnerable to cellular injury
1. DNA
2. Cell membranes
3. Protein generation
4. Adenosine triphosphate (ATP) production
Mechanisms of cellular injury
1. Hypoxia
• Decreased oxygen results in decreased production of ATP. ATP is normally
required by the Na/K pump and Ca2 pump.
• When ATP levels decrease, these pumps fail and sodium (along with water,
which follows sodium) enters the cell, causing swelling.
• Also, calcium enters the cell, which activates endonucleases, proteases,
phospholipases, and DNAses, which damage the cell.
• Cells switch to anaerobic respiration to produce ATP, which results
in accumulation of lactic acid.
• The accumulation of lactic acid decreases the cellular PH. Decreased pH causes
disaggregation of ribosomes from endoplasmic reticulum.
Cont’d
2. Generation of oxygen-derived free radicals (reactive oxygen species)
by a stressing agent

• A free radical is a molecule with an unpaired electron in the outer

orbit

• Free radicals are generated by normal physiologic reduction-oxidation

reactions, UV light, x-rays and ionizing radiation, Transitive metals
e.g.H2O2 +Fe3+ Fe3+OH+OH and exogenous chemicals
Cont’d
• Effects of free radicals
-Lipid peroxidation
1. damages cell membranes which increases apoprotein synthesis and
results in fatty liver
2. Cell swelling which results in influx of Ca+2 and inactivation of
mitochondria, cell enzymes and denaturation of proteins
- DNA fragmentation
- Protein cross-linking (e.g. sulfhydryl groups) resulting increased
degradation and decreased activity
Cont’d
Methods to prevent formation of reactive
oxygen species

• Catalase - which degrades hydrogen peroxide.

• Superoxide dismutase - which converts superoxide to hydrogen
peroxide
• Glutathione - which catalyzes breakdown of hydroxyl radicals.
• Vitamins A, C, and E - which have an antioxidant effect
Cont’d
Cont’d
3. Chemical injury:

• Some chemicals are directly toxic to the cells and others require
conversion to a toxic metabolite
• E.g. Ethylene glycol (antifreeze) is not toxic, but its metabolite, oxalic
acid is. In contrast, cyanide directly inactivates cytochrome oxidase,
which impairs the formation of ATP.
Cont’d
4. Increased mitochondrial cytosolic calcium:
• Increased mitochondrial cytosolic calcium leads to lipid peroxidation
and formation of mitochondrial permeability transition (a nonselective
pore that dissipates the proton gradient)

• Also, increased mitochondrial cytosolic calcium causes release of

cytochrome c, which in turn activates apoptosis
Reversible cell injury
• characterized by functional and structural alterations in early stages
or mild forms of injury, which are correctable if the damaging stimulus
is removed
• Generalized swelling of the cell and its organelles. The decreased
production of ATP causes sodium to enter the cell, bringing water and
causing cellular and organelle swelling
• Fatty change occurs in organs that are actively involvedin lipid
metabolism (e.g., liver). Manifested by the appearance of
lipidvacuoles in the cytoplasm
Irreversible cell injury
• This type of injury occurs with damage to plasma or lysosomal
membranes, loss of DNA, or loss of mitochondria.

• In these cases, the damage cannot be reversed

• The two most important factors determining irreversible

damage are membrane disturbances and the inability to reverse
mitochondrial dysfunction.
Morphologic changes of cellular injury
 light microscope morphologic changes of cell injury
• Reversible injury: Cellular swelling and fatty change.

• Irreversible injury: Nuclear karyolysis (loss of basophilia), pyknosis

(shrinkage of nucleus), and karyorrhexis (fragmentation of nucleus).
Cont’d
 Electron microscope morphologic changes of cellular injury
• Reversible injury: Cellular blebs and small mitochondrial densities

• Irreversible injury: Ruptured lysosomes, myelin figures (which indicate

phospholipid precipitation), lysis of endoplasmic reticulum, and large
calcium rich mitochondrial densities
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A. Normal kidney tubules with viable epithelial cells
B. Early (reversible) ischemic injury showing surface blebs,increased eosinophilia of cytoplasm, and swelling of
occasional cells
C. Necrotic (irreversible) injury of epithelial cells, with fragmentation and nuclear loss and leakage of contents
Electron micrograph of a normal epithelial
cell of the proximal kidney tubule.
Epithelial cell of the proximal tubule showing irreversible cell
injury resulting from reperfusion following ischemia
Irreversible proximal tubular cell injury
Cont’d
The End