Download Cell Injury

Today’s Quranic verse
But to those who believe and do deeds of
righteousness, He will give their (due)
rewards, and more, out of His bounty: But
those who are disdainful and arrogant, He
will punish with a grievous penalty; Nor will
they find, besides God, any to protect or help
them. [004:173]
CELL INJURY
Principles of Cell Injury
• Dependent upon the etiology, duration, and severity of the inciting
injury
• Dependent upon cell type, stage of cell cycle, and cell adaptability
• Cellular membranes, mitochondria, endoplasmic reticulum, and the
genetic apparatus are particularly vulnerable
• Injury at one focus often has a cascade effect
• Morphologic reactions occur only after critical biochemical
(molecular) damage
Normal cell is in a steady state “Homeostasis”
Change in Homeostasis due to stimuli - Injury
Response to Injury –
Reversible (adaptation)/ Irreversible (cell death)
Adaptive Responses:
– Atrophy
– Hypertrophy
– Hyperplasia
– Metaplasia
Reversible vs. Irreversible Injury
Cell injury is a continuum, and it is not possible to identify the exact
point at which injury becomes irreversible.
However, some ultrastructural and light microscopic changes are
associated with each form of injury.
Once an irreversible injury occurs, the cell undergoes necrosis,
which is the light-microscopic hallmark of cell death.
In general, permanent organ injury is associated with the death of
individual cells.
By contrast, the cellular response to persistent sub-lethal injury,
whether chemical or physical, reflects adaptation of the cell to a
hostile environment. These changes are, for the most part,
reversible on discontinuation of the stress”
If the acute stress to which a cell must react exceeds its ability to
adapt, the resulting changes in structure and function lead to the
death of the cell
Causes of Cell Injury
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Hypoxia
Physical agents including Radiations
Chemicals and Drugs
Microbiologic Agents
Immunologic Reactions
Genetic Defects
Nutritional Imbalances
Mechanisms of Cell Injury
Mechanisms of Cell Injury
• Ischemia/Hypoxia
• Activated Oxygen Species(O2.-, H2O2, OH. )
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Radiation
Inflammation
Oxygen toxicity
Chemicals
Reperfusion injury
Others
Chemicals
Infectious agents
Mechanical disruption
Deficiency of essential metabolites
Damage to DNA
MECHANISMS OF CELL INJURY
ISCHEMIC AND HYPOXIC
INJURY
Reversible Injury
- Decreased oxidative phosphorylation
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reduced ATP
increased cytosolic free calcium
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reduced activity of “sodium pump”
accumulation of sodium by cell
is-osmotic gain of water (swelling)
diffusion of potassium from cell
- Increased Cytosolic Calcium (activates enzymes)
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ATPase
decreased ATP
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Phospholipase
decreased phospholipids
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Endonuclease
nuclear chromatin damage
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Protease
disruption of membrane and cytoskeletal proteins
- Increased anaerobic glycolysis
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glycogen depletion
lactic acid accumulation
accumulation of inorganic phosphates
reduced intracellular pH
- Detachment of ribosomes
• reduced protein synthesis
- Worsening mitochondrial function
- Increasing membrane permeability
- Cytoskeleton dispersion
• loss of microvilli
• formation of cell surface blebs
Reversible Injury results in
– Swelling of mitochondria, endoplasmic reticulum,
and entire cells
Irreversible Injury
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Mitochondrial changes
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severe vacuolization
amorphous calcium-rich densities
Extensive plasma membrane damage
Prominent swelling of lysosomes
Massive influx of calcium (on reperfusion)
Continued loss of cell proteins, coenzymes, ribonucleic
acids and other metabolites
Leakage of enzymes measured in serum
– Injury to lysosomal membranes
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leakage of degradative enzymes
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activation of acid hydrolases due to reduced intracellular pH with
degradation of cell components
– Prominent leakage of cellular enzymes
– Influx of macromolecules from interstitium
– “Myelin figures”-whorled phospholipid masses
FREE RADICAL MEDIATION OF CELL INJURY
• Free Radical Injury Contributes to:
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Chemical and radiation injury
Oxygen and other gaseous toxicity
Cellular aging
Microbial killing by phagocytic cells
Inflammatory damage
Tumor destruction by macrophages
Others
• Definition Of Free Radicals
– Extremely unstable, highly reactive chemical species with
a single unpaired electron in an outer orbital
• Examples Of Free Radicals
– OH., H., O2.-
• Source of Free Radicals
– Hydrolysis of water into OH. and H. by ionizing radiation
– Redox reactions in normal physiology
• respiration
• intracellular oxidase action
• transition metal reactions
– Metabolism of exogenous chemicals
• Free Radical Injury Mechanisms
– Lipid peroxidation of membranes
• double bonds in polyunsaturated lipids
– Lesions in DNA
• reactions with thymine with single-strand breaks
– Cross-linking of proteins
• sulfhydryl-mediated protein cross-linking
• Free Radical Degradation
– Unstable with spontaneous decay
– Decay accelerated by
• superoxide dismutase
• glutathione
• Catalase
– Antioxidants (vitamin E, ceruloplasmin)
• block formation or scavenge
CHEMICAL INJURY
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cause:
Injury to cell membrane and other cell structures
Block enzyme pathways (e.g cyanide)
Coagulate cell proteins
Upset concentration gradients and pH
Direct action or Conversion to reactive toxic metabolite
RADIATION INJURY
Causes:
Immediate cell death
Interuption of cell replication (cancer cells)
Mutation (thymidine dimers)
Non-ionizing radiations can cause thermal injury
BIOLOGICAL AGENTS CAUSING INJURY
Viral injury
• Direct cytotoxicity
• Indirect cytotoxicity, via the immune system (activated killer
T cells identify viral proteins on the cell surface and kill the
cell)
Bacterial injury
• Mostly due to their metabolic products & secretions
• Host inflammatory reaction