Reversible and Irreversible Cell Injury

• Cell injury's earliest changes involve decreased ATP generation, loss of cell membrane integrity, protein synthesis defects, cytoskeletal damage, and DNA damage.
• Within limits, cells can compensate for these issues, reversing damage if the stimulus is removed.

Reversible vs. Irreversible Cell Injury

• Persistent or excessive injury causes cells to pass a threshold into irreversible injury.
• Irreversible injury is characterized by severe mitochondrial vacuolization, extensive plasma membrane damage, lysosome swelling, and amorphous mitochondrial densities.
• Two key features consistently define irreversible injury: the inability to reverse mitochondrial dysfunction and a profound loss of membrane function.

Patterns of Reversible Cell Injury

• Cell swelling
• Fatty change

Morphology of Reversible Cell Injury

Cell Swelling

• The first sign of cell injury.
• Manifests as small, clear vacuoles in the cytoplasm.
• Also known as hydropic change or vacuolar degeneration.

Fatty Change

• Show the presence of lipid vacuoles in the cytoplasm.
• Commonly affects the liver.
• Causes include hypoxic injury, toxins (alcohol), metabolic issues (diabetes mellitus), and malnutrition.

Ischemic Cell Injury

• As oxygen levels decrease, oxidative phosphorylation is lost, and ATP generation decreases.
• Sodium pump failure occurs, leading to potassium loss, sodium and water influx, and cell swelling as a result.
• Glycogen is progressively lost, protein synthesis decreases, and intracellular pH decreases.
• Continued hypoxia worsens ATP depletion, causing further deterioration, such as loss of microvilli and formation of "blebs" on the cell surface.
• "Myelin figures" may appear in the cytoplasm or extracellularly.
• All of these disturbances are reversible if oxygen is restored.
• If ischemia persists, irreversible injury and necrosis occur.
• Irreversible injury is morphologically associated with severe mitochondrial swelling, extensive plasma membrane damage, and lysosome swelling.
• Large, flocculent, amorphous densities develop in the mitochondrial matrix.
• Dead cells are phagocytosed by other cells.

Ischemia-Reperfusion Injury

• Restoration of blood flow to reversibly injured ischemic tissues can allow cell recovery.
• Ischemia-reperfusion injury is clinically relevant in conditions like myocardial infarction and stroke.
• New damaging processes are initiated during reperfusion, potentially killing cells that might have otherwise recovered.
• Reoxygenation may trigger increased generation of oxygen free radicals from parenchymal and endothelial cells and infiltrating leukocytes.
• Reactive oxygen species can further promote mitochondrial permeability transition.
• Ischemic injury is associated with inflammation due to cytokine production and increased adhesion molecule expression by hypoxic cells.
• This recruits polymorphonuclear leukocytes, causing additional injury.
• Activation of the complement pathway may contribute to ischemia-reperfusion injury.

Irreversible Cell Injury (Cell Death)

• Accidental cell death (necrosis)
• Programmed cell death (apoptosis)

Necrosis

• Refers to morphologic changes following cell death in living tissue due to enzymatic degradation.
• Occurs in irreversible injury.
• May elicit inflammation in surrounding tissue.
• Involves denaturation of intracellular proteins and enzymatic digestion of the cell.
• Enzymes come from lysosomes of the dead cells (autolysis) or immigrant leukocytes during inflammation.

Morphology of Necrosis

• Necrotic cells show increased eosinophilia with a glassy, homogeneous appearance.
• The cytoplasm becomes vacuolated and appears moth-eaten.
• Calcification of dead cells may occur.

Nuclear Changes in Necrosis

• Due to nonspecific DNA breakdown.
• Karyolysis: fading of chromatin basophilia.
• Pyknosis: (also seen in apoptosis) nuclear shrinkage and increased basophilia.
• Karyorrhexis: fragmentation of the nucleus.
• The nucleus in the necrotic cell totally disappears over time.

Electron Microscopy of Necrotic Cells

• Overt discontinuities in the plasma membrane.
• Marked dilation of mitochondria with large amorphous densities.
• Intracytoplasmic myelin figures.
• Amorphous osmiophilic debris.
• Aggregates of fluffy material, likely denatured protein.

Types of Necrosis

• Coagulative necrosis
• Liquefactive necrosis
• Caseous necrosis
• Fat necrosis

Coagulative Necrosis

• The basic outline of the coagulated cell is preserved for days.
• Affected tissues have a firm texture.
• Necrotic cells are removed by fragmentation, phagocytosis, and proteolytic lysosomal enzymes.
• Characteristic of hypoxic death in all tissues except the brain.

Liquefactive Necrosis

• Characteristic of focal bacterial or fungal infections.
• Also seen in hypoxic death of cells within the central nervous system.
• Completely digests dead cells, transforming tissue into a liquid viscous mass.
• May be creamy yellow due to dead white cells (pus) if initiated by acute inflammation.

Gangrenous Necrosis

• Term used by surgeons, usually referring to a limb with lost blood supply and coagulative necrosis.
• "Wet gangrene" occurs when bacterial infection is superimposed.

Caseous Necrosis

• A type of coagulative necrosis seen in tuberculous infection.
• The necrotic area appears as cheesy white granular debris surrounded by granuloma.

Fat Necrosis

• Focal areas of fat destruction due to released pancreatic lipases.
• Occurs in acute pancreatitis.
• Released fatty acids combine with calcium to form chalky white areas (fat saponification).
• Histologically, shows shadowy outlines of necrotic fat cells with basophilic calcium deposits, surrounded by inflammation.

Gangrene

• Definition: Necrosis of large tissue with putrefaction, black, foul-smelling appearance.
• Pathogenesis: Necrotic tissue is infected with putrefactive organisms.
• Hemoglobin + hydrogen sulfide (from bacteria) yields iron sulfide (black color).

Types of Gangrene

Dry Gangrene

• Occurs only on the skin surface, typically on limbs (especially toes).
• Cause: Arterial obstruction.
• Common in people with impaired peripheral blood flow, such as diabetics.
• Appears dry, shrunken, and dark reddish-black, resembling mummified flesh.

Wet Gangrene

• Affects the small intestine, appendix, lung, and uterus.
• Cause: Both arterial and venous obstruction.
• Appears wet, swollen, foul-smelling, black or green.
• Toxic bacterial products are absorbed, causing systemic signs of septicemia and death.

Gas Gangrene

• Affects deep contaminated wounds with muscle damage.
• War wounds.
• Lesions are swollen with gas bubble formation.

Apoptosis

• Programmed cell death.
• Intracellular program is tightly regulated, cells activate their own enzymes to degrade DNA, nuclear proteins, and cytoplasmic proteins.
• The plasma membrane remains intact, but its structure is altered to signal macrophages for phagocytosis.
• The dead cell is rapidly cleared before contents leak out, so there is no inflammation.
• Apoptosis and necrosis can sometimes coexist.

Causes of Apoptosis

• Apoptosis means "falling off."
• It eliminates unwanted, harmful, or outlived cells.
• It is also a pathologic event for irreparably damaged cells, especially with DNA damage.
• Apoptosis can be physiologic, adaptive, and pathologic.

Apoptosis in Physiologic Situations

• Programmed destruction of cells during embryogenesis.
• Hormone-dependent involution in adults.
• Cell deletion in proliferating cell populations.
• Death of host cells that have served their purpose.
• Elimination of potentially harmful self-reactive lymphocytes.
• Cell death induced by cytotoxic T cells.

Apoptosis in Pathologic Conditions

• Cell death due to injurious stimuli that damage DNA.
• Cell injury in certain viral diseases, such as viral hepatitis.
• Pathologic atrophy in parenchymal organs after duct obstruction.
• Cell death in tumors.

Morphology of Apoptosis

• Cell shrinkage
• Chromatin condensation: The most characteristic feature.
• The nucleus may break up into fragments.
• Formation of cytoplasmic blebs and apoptotic bodies.
• Phagocytosis of apoptotic cells or cell bodies by macrophages.

Histological Examination of Apoptosis

• Involves single cells or small clusters of cells.
• The apoptotic cell appears as a round or oval mass of intensely eosinophilic cytoplasm with dense nuclear chromatin fragments.
• There is no inflammation.

Comparison of Necrosis and Apoptosis

Necrosis

• Cell size: Enlarged (swelling)
• Nucleus: Pyknosis → karyorrhexis → karyolysis
• Plasma membrane: Disrupted
• Cellular contents: Enzymatic digestion; may leak out
• Adjacent inflammation: Frequent
• Role: Invariably pathologic

Apoptosis

• Cell size: Reduced (shrinkage)
• Nucleus: Fragmentation into nucleosome-size fragments
• Plasma membrane: Intact; altered structure
• Cellular contents: Intact; may be released in apoptotic bodies
• Adjacent inflammation: No
• Role: Often physiologic; may be pathologic

Cell injury occurs when cells face stress. Early changes involve decreased ATP, membrane integrity loss, and DNA damage. Reversible injury can recover, but irreversible injury leads to severe mitochondrial and membrane damage.