17.1 Cell Injury, Inflammation & Repair

17.1 Cell Injury, Inflammation & Repair

Quick Answer: Reversible injury = swelling/fatty change; irreversible = membrane + nuclear death. Necrosis pattern names the organ/mechanism. Apoptosis uses intrinsic (mito/caspase-9) or extrinsic (death receptor/caspase-8) arms. Acute inflammation is neutrophil-driven; chronic is mono/lymph with possible granulomas. Regeneration needs intact stroma; otherwise scar.

Multisystem CBSE items test whether you can classify cell death, name the inflammatory phase, and predict healing outcome from the same vignette. Build a decision tree: is the cell still salvageable, what death pattern is shown, which leukocyte dominates, and will architecture return or fibrose?

Reversible vs Irreversible Cell Injury

Injury severity and duration determine whether a cell recovers or dies. Reversible injury reflects ATP depletion and membrane pump failure without catastrophic structural collapse. Classic light-microscopic findings are cellular swelling (hydropic change) from Na+/K+-ATPase failure and water influx, and fatty change (steatosis) when lipid export or oxidation fails (classic in hypoxic or toxic hepatocytes). Organelles may show blebbing, ER dilation, and mitochondrial swelling, but the plasma membrane remains intact enough to prevent enzyme spill and the nucleus does not undergo necrotic dissolution.

Irreversible injury occurs when mitochondrial damage becomes permanent (high-conductance permeability transition pore, severe cytochrome c release), membrane integrity is lost, and calcium floods the cytosol activating destructive phospholipases, proteases, and endonucleases. Hallmarks include severe membrane damage, lysosomal rupture, mitochondrial amorphous densities, and nuclear changes of necrosis: pyknosis (shrinkage/condensation), karyorrhexis (fragmentation), and karyolysis (fading/dissolution). Clinically, irreversible injury of organs rich in enzymes produces serum markers (troponin, ALT/AST, amylase/lipase, CK) once membranes leak.

Hypoxia and ischemia are the most common systemic triggers. Ischemia is worse than pure hypoxia because it also removes substrates and prevents waste clearance. Toxins, free radicals, immune attack, physical agents, and nutritional deficiency complete the classic injurious list.

Necrosis Patterns

Necrosis is pathologic cell death in living tissue, always accompanied eventually by inflammation. Pattern recognition is high-yield because CBSE stems often give organ + gross/micro clue rather than the word “necrosis.”

Coagulative necrosis preserves tissue architecture as ghost cells with eosinophilic cytoplasm and lost nuclei. It is the default pattern of ischemic infarction in solid organs (heart, kidney, spleen) excluding brain. Early myocardial infarct is the prototype: hypereosinophilic fibers, then neutrophil influx.

Liquefactive necrosis digests tissue into a liquid viscous mass. It dominates brain infarcts (abundant hydrolytic enzymes from lipids/glia) and abscesses (neutrophil enzymes). Pus is liquefactive debris + neutrophils.

Caseous necrosis is soft, white, cheese-like debris with complete architectural obliteration, classically in tuberculous granulomas (and some fungal granulomas). Microscopically it is amorphous eosinophilic material surrounded by epithelioid macrophages and giant cells.

Fat necrosis follows pancreatic lipase release (acute pancreatitis) or trauma (breast). Free fatty acids saponify with calcium → chalky white deposits; basophilic calcium on H&E.

Fibrinoid necrosis is bright pink, amorphous fibrin-like material in vessel walls from immune complex deposition or severe hypertension (malignant HTN, polyarteritis nodosa, type III hypersensitivity in vessels).

Gangrenous necrosis is a clinical term for limb (or gut) ischemia: dry gangrene is mostly coagulative; wet gangrene adds bacterial liquefaction and gas/putrefaction (clostridial gas gangrene is a special infectious form).

Apoptosis: Intrinsic and Extrinsic Pathways

Apoptosis is regulated, energy-dependent programmed cell death that removes cells with minimal inflammation (apoptotic bodies phagocytosed cleanly). Physiologic uses include embryogenesis, hormone-dependent involution, and deletion of self-reactive lymphocytes. Pathologic uses include DNA damage, viral infection, and atrophy after duct obstruction.

Intrinsic (mitochondrial) pathway: Cellular stress (DNA damage, growth factor withdrawal, hypoxia) shifts Bcl-2 family balance. Pro-apoptotic Bax/Bak open mitochondrial outer membrane; anti-apoptotic Bcl-2/Bcl-xL oppose them. Cytochrome c enters cytosol, forms the apoptosome with Apaf-1, and activates caspase-9, which activates executioner caspases-3/6/7. p53 after DNA damage transcriptionally favors pro-apoptotic members—linking tumor suppression to apoptosis failure when p53 is lost.

Extrinsic (death receptor) pathway: Ligands such as FasL or TNF bind Fas (CD95) or TNFR. Death domains recruit FADD and activate caspase-8 (or -10), which again cleaves executioner caspases. Some cells amplify via Bid cleavage linking extrinsic to mitochondrial release.

Morphology: cell shrinkage, chromatin condensation, membrane blebbing, apoptotic bodies; no robust neutrophilic reaction. TUNEL and caspase cleavage assays are laboratory correlates, not usually required beyond concept.

Free Radical Injury and Ischemia-Reperfusion

Reactive oxygen species (ROS)—superoxide, hydrogen peroxide, hydroxyl radical—damage lipids (peroxidation), proteins, and DNA. Sources include mitochondria, NADPH oxidase in leukocytes (respiratory burst), radiation, and metabolism of toxins (CCl4 → CCl3• in liver). Defenses: superoxide dismutase, catalase, glutathione peroxidase, vitamins C/E, and glutathione.

Ischemia-reperfusion injury worsens tissue damage when blood flow returns: restored O2 fuels ROS generation from damaged mitochondria and activated neutrophils; complement may activate; inflammation intensifies. Clinically relevant after thrombolysis, transplant reperfusion, and shock resuscitation. Antioxidant systems and controlled reperfusion concepts appear in mechanism stems.

Amyloid

Amyloid is misfolded β-pleated sheet protein deposited extracellularly, Congo red–positive with apple-green birefringence under polarized light. Types to map:

Systemic AL/AA cause organomegaly, restrictive cardiomyopathy, nephrotic syndrome, and macroglossia depending on distribution. Local amyloid is disease-specific (e.g., Aβ in brain).

Acute Inflammation: Cellular Events and Mediators

Acute inflammation is the rapid vascular and cellular response to injury or infection, dominated early by neutrophils.

Vascular events: Transient vasoconstriction, then arteriolar vasodilation (rubor, calor) mediated by histamine, NO, prostaglandins. Increased permeability (histamine, bradykinin, leukotrienes, C3a/C5a) produces exudate and swelling (tumor); pain (dolor) from bradykinin and PGE2; loss of function follows.

Leukocyte recruitment sequence:

1. Margination and rolling — selectins (E/P on endothelium, L on leukocytes) bind sialylated ligands (Sialyl-Lewis X).
2. Firm adhesion — integrins (LFA-1, Mac-1, VLA-4) bind ICAM-1/VCAM-1 upregulated by TNF and IL-1.
3. Transmigration (diapedesis) — PECAM-1 (CD31) at junctions.
4. Chemotaxis — C5a, LTB4, IL-8 (CXCL8), bacterial products (fMLP), kallikrein.
5. Phagocytosis and killing — opsonins IgG and C3b; killing via ROS (NADPH oxidase → superoxide) and lysosomal enzymes; myeloperoxidase generates HOCl in neutrophils.

Defects map to disease: LAD (integrin/selectin pathway) → high neutrophils in blood, poor pus, delayed cord separation; Chediak-Higashi → microtubule defect, giant granules, impaired chemotaxis/degranulation; CGD → NADPH oxidase defect, catalase-positive infections, negative NBT/DHR.

Chronic Inflammation and Granulomatous Disease

Chronic inflammation features mononuclear cells (macrophages, lymphocytes, plasma cells), tissue destruction, and attempts at healing with fibrosis and angiogenesis. Drivers include persistent infection (TB, fungi), prolonged toxin exposure, and autoimmunity.

Granulomatous inflammation is a patterned chronic response: aggregates of epithelioid macrophages ± multinucleated giant cells, often with a lymphocyte rim, ± central necrosis (caseating vs noncaseating).

IFN-γ from Th1 cells activates macrophages; TNF maintains granuloma integrity—anti-TNF therapy can reactivate latent TB. Differential diagnosis of granulomas is a classic multisystem stem (lungs, nodes, gut, skin).

Tissue Repair vs Regeneration; Scarring

Regeneration restores normal cells and architecture when the connective tissue framework remains intact and the cell population can divide (labile tissues: epithelium, bone marrow; stable tissues: liver, kidney tubules, endothelium—can re-enter cell cycle). Complete recovery after mild acute tubular injury or partial hepatectomy exemplifies regeneration.

Repair by connective tissue (scarring) occurs when the framework is destroyed, injury is extensive, or the tissue is permanent (neurons, skeletal and cardiac muscle have negligible regenerative capacity for functional parenchyma). Steps of scar formation: inflammation → granulation tissue (fibroblasts, new vessels, loose ECM) → collagen deposition and remodeling (type III → type I collagen; MMPs and TIMPs). Wound strength rises over weeks; keloids and hypertrophic scars reflect excess collagen.

Growth factors: EGF, TGF-α, PDGF, FGF, VEGF (angiogenesis), TGF-β (fibrosis, anti-inflammatory). Vitamin C deficiency impairs collagen cross-linking (scurvy, wound dehiscence); zinc deficiency and steroids impair healing; infection and foreign bodies delay closure.

Integration for CBSE Vignettes

When a stem describes chest pain with coagulative necrosis and neutrophils at day 1–3 of MI, map timeline of inflammation and enzyme leak. When a lung biopsy shows caseating granulomas, think mycobacteria/fungi before sarcoid. When a cell dies without inflammation after DNA damage, think apoptosis and p53/Bcl-2. When reperfusion after embolectomy worsens markers, invoke ROS. Multisystem score comes from stacking these modules cleanly rather than memorizing isolated facts.