Cell Injury and Cellular Adaptation Vocabulary Flashcards

Overview and General Principles of Cell Injury

• Types of cellular responses to injury:

  • Cellular adaptations

  • Cell injury (Reversible cell injury and Irreversible cell injury)

  • Intracellular accumulations

  • Pathologic calcification

• Definition of cell injury: A sequence of events that occurs if the limits of adaptive capability are exceeded or if no adaptive response is possible.

• Principles governing cellular response to injury:

  • The cellular response to injury is not an all-or-nothing phenomenon.

  • The response to a given stimulus depends on the type, status, and genetic make-up of the injured cell.

  • The response depends on the type, duration, and severity of the injury.

  • Cells are complex interconnected systems; a single local injury can result in multiple secondary and tertiary effects.

  • Cell function is lost far before biochemical manifestations become detectable, and biochemical changes occur before morphological manifestations of injury become detectable.

Etiology and Causes of Cell Injury

• Genetic causes:

  • Developmental defects (errors in morphogenesis)

  • Cytogenetic defects (chromosomal abnormalities)

  • Single gene defects (Mendelian disorders)

  • Multifactorial inheritance disorders

• Acquired causes:

  • Hypoxia: Caused by ischaemia, anemia, carbon monoxide poisoning, or cardiorespiratory failure.

  • Physical agents: Mechanical trauma, thermal injury (extreme heat or cold), radiation, electric shock, and atmospheric pressure changes.

  • Chemical agents and drugs: Heavy metals, acids, alkalies, insecticides, herbicides, alcohol, and smoking.

  • Microbial agents: Bacteria, viruses, fungi, rickettsiae, and parasites.

  • Immunological agents: Autoimmunity and hypersensitivity reactions.

  • Nutritional imbalances: Deficiencies of protein, calories, trace elements, or vitamins; excess cholesterol.

  • Psychological factors.

  • Aging.

General Biochemical Mechanisms of Cell Injury

• Loss of energy: Depletion of ATP and depletion of $O_2$.

• Mitochondrial damage: Known as "permeability transition".

• Loss of calcium homeostasis.

• Defects in plasma membrane permeability.

• Generation of reactive oxygen species ($O_2^{\bullet}$, $H_2O_2$, $OH^{\bullet}$) and other free radicals.

Free Radical-Induced Cell Injury

• Properties of free radicals:

  • Chemical species containing a single unpaired electron in an outer orbital.

  • Chemically unstable, readily reacting with organic and inorganic molecules (proteins, lipids, and carbohydrates) located mainly in cell membranes and nucleic acids.

  • Initiate autocatalytic reactions, wherein molecules reacting with free radicals are themselves converted into free radicals.

• Intracellular sources of free radicals:

  • Normal intracellular redox reactions.

  • Nitric oxide ($NO$), which can act directly as a free radical.

  • Ionizing radiation (UV light, X-rays), which hydrolyzes water into hydroxyl ($OH^{\bullet}$) and hydrogen ($H^{\bullet}$) free radicals.

  • Metabolism of exogenous chemicals, such as carbon tetrachloride ($CCl_4$).

  • Physiological antimicrobial reactions during normal immune responses.

• Neutralization mechanisms for free radicals:

  • Spontaneous decay.

  • Superoxide dismutase (SOD): $2O_2^{\bullet} + 2H^+ \rightarrow O_2 + H_2O_2$

  • Glutathione (GSH): $2OH^{\bullet} + 2GSH \rightarrow 2H_2O + GSSG$

  • Catalase: $2H_2O_2 \rightarrow O_2 + H_2O$

  • Endogenous and exogenous antioxidants: Vitamin E, Vitamin A, Vitamin C, and $\beta$-carotene.

• Mechanisms of free radical-induced injury:

  • Lipid peroxidation of membranes: Double bonds in polyunsaturated membrane lipids are attacked by oxygen free radicals.

  • DNA fragmentation: Free radicals react with thymine in nuclear and mitochondrial DNA, yielding single-strand breaks.

  • Protein cross-linking: Sulfhydryl-mediated protein cross-linking results in accelerated degradation or loss of enzymatic activity.

Reversible Cell Injury and Reversible Hypoxic/Ischemic Cascade

• Biochemical sequence of reversible hypoxic and ischemic injury:

  • Ischemia leads to decreased mitochondrial oxidative phosphorylation, resulting in decreased ATP generation.

  • Failure of $\text{Na}^+/\text{K}^+$ ATPase membrane pumps:

  • Causes loss of ionic and osmotic gradients.

  • Leads to influx of $\text{Ca}^{2+}$, $\text{H}_2\text{O}$, and $\text{Na}^+$, accompanied by efflux of $\text{K}^+$.

  • Results in cellular swelling, loss of microvilli, cytoplasmic blebbing, swelling of the endoplasmic reticulum (ER), and formation of myelin figures.

  • Increased anaerobic glycolysis:

  • Leads to glycogen depletion and accumulation of lactate.

  • Results in decreased intracellular pH, which induces clumping of nuclear chromatin and lipid deposition (fatty change).

  • Detachment of ribosomes:

  • Detachment of ribosomes from the rough endoplasmic reticulum (RER) and disaggregation of polysomes leads to decreased protein synthesis.

• Morphological features of reversible cell injury:

  • Cellular swelling (hydropic change or vacuolar degeneration): The first manifestation of almost all forms of cell injury.

  • Fatty change: Accumulation of lipid vacuoles within the cytoplasm.

  • Plasma membrane alterations: Bleb formation, blunting and distortion of microvilli, formation of myelin figures, and loosening/deterioration of intercellular attachments.

  • Mitochondrial changes: Early condensation resulting from matrix protein loss after ATP depletion, followed by swelling due to ionic shifts, and presence of small amorphous densities.

  • Endoplasmic reticulum changes: ER dilatation, detachment of ribosomes, and disaggregation of polysomes with progressive fragmentation and myelin figure formation.

  • Lysosomal changes: Late swelling, fusion with autophagic vacuoles (phagosomes), rupture, and eventual disappearance.

  • Nuclear changes: Clumping of nuclear chromatin.

Specific Patterns of Cell Degeneration and Intracellular Accumulations

• Cloudy swelling / Hydropic swelling / Parenchymatous degeneration:

  • Etiology: Infection, toxic/physico-chemical injury, ischemia, or hypokalemia resulting from severe vomiting or diarrhea.

  • Pathophysiology: Failure of the cellular sodium pump allows excess $\text{Na}^+$ to enter cells, causing an influx of cellular water.

  • Gross findings: Pallor, increased turgor, and increased organ weight.

  • Microscopic findings: Cell swelling, coarse granular cytoplasm, narrow lumen with conical cells (as seen in kidney pathology), normal nucleus under light microscopy, and presence of pigmented or hyaline casts.

• Fatty degeneration (Steatosis or Fatty Metamorphosis):

  • Definition: Abnormal appearance of fat within parenchymal cells.

  • Etiology: Hepatotoxic agents ($C_2H_5OH$, chloroform, $CCl_4$), severe infections, prolonged anemia, and toxemia of pregnancy.

  • Pathophysiology in the liver:

  • Inability of hepatocytes to synthesize phospholipids.

  • Decreased lipoprotein release from hepatocytes.

  • Increased triglyceride production.

• Hyaline degeneration:

  • Zenker's waxy hyaline masses: Associated with typhoid fever and Weil's disease (leptospirosis).

  • Mallory bodies: Associated with nutritional cirrhosis.

  • Russell bodies: Associated with chronic inflammation.

  • Crooke's hyaline bodies: Associated with Cushing's syndrome.

  • Councilman bodies: Associated with yellow fever and viral hepatitis.

• Mucinous degeneration (Mucoid degeneration):

  • Definition: Excessive accumulation of mucus in unusual locations (e.g., colon).

  • Neoplastic implication: Cancers exhibiting severe mucinous degeneration are termed mucinous carcinoma or colloid carcinoma.

  • Mucin subtypes: True mucin and paramucin.

• Lipoidal degeneration:

  • Pathological manifestation seen in vascular structures such as the aorta.

Irreversible Cell Injury and Necrosis

• Definition of necrosis: Death and subsequent degradation of cells in living tissue, resulting from severely disturbed extracellular environmental conditions and enzymatic digestion.

• Transition from reversible to irreversible injury:

  • Depends on the extent of ATP depletion and membrane dysfunction, particularly of mitochondria.

  • ATP depletion results in loss of the mitochondrial $H^+$ gradient and release of cytochrome c.

  • Intracellular $\text{Ca}^{2+}$ influx activates:

  • Membrane phospholipases: Induces loss of membrane phospholipids and membrane damage.

  • Intracellular proteases: Causes cytoskeletal degradation and alterations.

  • Accumulation of phospholipid degradation products: Directly toxic to the cell.

  • Lysosomal enzyme release: Decreased pH and lysosomal rupture release hydrolytic enzymes, causing autolysis and nuclear degradation.

• Fundamental processes underlying necrosis morphology:

  • Denaturation of proteins.

  • Enzymatic digestion of cell components.

• Nuclear patterns in necrotic cells:

  • Pyknosis: Nuclear shrinkage characterized by a shrunken, intensely basophilic nucleus resembling an ink drop.

  • Karyolysis: Progressive fading of nuclear basophilic staining leading to "ghost" nuclei.

  • Karyorrhexis: Fragmentation of the shrunken nucleus into numerous smaller fragments.

• Cytoplasmic changes in necrotic cells: Increased eosinophilia.

Morphological Patterns and Types of Necrosis

• Coagulative necrosis:

  • Gross appearance: Pale.

  • Histological appearance: Architecture is preserved, but cells appear "ghost-like".

• Liquefactive necrosis:

  • Gross appearance: Soft.

  • Histological appearance: Complete loss of structural detail; cellular components are totally destroyed.

• Caseous necrosis:

  • Gross appearance: Cheesy or crumbly.

  • Histological appearance: Messy, acellular debris surrounded by macrophages.

• Gangrenous necrosis:

  • Gross appearance: Usually dry and dark.

  • Histological appearance: "Ghost-like" structural preservation often accompanied by large saprophytic bacteria.

• Enzymatic fat necrosis:

  • Gross appearance: Chalky white deposits.

  • Histological appearance: Amorphous pink and blue deposits with necrotic fat cells.

• Fibrinoid necrosis:

  • Deposition of fibrin-like proteinaceous material in vessel walls and tissues.

• Gummatous necrosis:

  • Characteristic necrotic pattern associated with spirochetal infections.

Apoptosis: Programmed Cell Death

• Definition: A genetically coordinated pattern of programmed cell death characterized by caspase activation that degrades nuclear DNA and proteins.

• Context: May occur under physiological or pathological conditions; does not elicit host inflammatory response.

• Morphological sequence:

  • Cell shrinkage and condensation of cytoplasm.

  • Chromatin condensation (pyknosis) and fragmentation (karyorrhexis).

  • Plasma membrane blebbing.

  • Formation of membrane-bound apoptotic bodies.

  • Rapid phagocytosis or lysis of apoptotic bodies by macrophages without release of cellular contents.

  • Light microscopy appearance: Round or oval mass with intensely eosinophilic cytoplasm and dense nuclear chromatin fragments.

• Physiological causes:

  • Embryogenesis and development: Removal of excess cells (e.g., disappearance of web tissues between fingers and toes).

  • Hormone withdrawal: Elimination of cells following withdrawal of hormonal stimuli (e.g., endometrial cell breakdown during the menstrual cycle).

  • Trophic stimulus withdrawal: Clearance of cells (e.g., neutrophils in acute inflammation, lymphocytes post-immune response).

  • Immunological tolerance: Elimination of potentially harmful clones of self-reactive lymphocytes.

• Pathological causes:

  • DNA damage: Radiation, cytotoxic drugs, or hypoxia activate p53; if repair fails, p53 triggers apoptosis. Mutated or absent p53 prevents apoptosis, predisposing to cancer.

  • Accumulation of misfolded proteins (ER stress): Mutations or free radical damage trigger ER stress, causing neurodegenerative diseases (Alzheimer, Huntington, Parkinson).

  • Viral infections: Direct viral induction (adenovirus, HIV) or host cytotoxic T lymphocyte response (viral hepatitis).

  • Neoplastic cells and graft rejection: T-cell-mediated elimination of tumors and cellular rejection of transplants.

  • Pathologic atrophy following duct obstruction: Duct blockages in parenchymal organs (pancreas, parotid gland, kidney).

• Molecular pathways of apoptosis:

  • Intrinsic (Mitochondrial) Pathway:

  • Activated by intracellular signals (growth factor withdrawal, DNA damage, ER stress, elevated free $\text{Ca}^{2+}$).

  • Permeability regulated by Bcl-2 family (>20 proteins):

    • Proapoptotic: Bax, Bak, Bid, Bad, Bik.

    • Anti-apoptotic: Bcl-2, Bcl-xL, Mcl-1 (prevent leakage of apoptotic proteins).

  • Mitochondrial outer membrane permeabilization releases cytochrome c.

  • Activates initiator caspase-9.

  • Extrinsic (Death Receptor-Initiated) Pathway:

  • Activated by extracellular ligands binding death receptors: Type 1 TNF receptor (TNFR1) and Fas (CD95).

  • Functions: Clearance of self-reactive lymphocytes (via FasL on T cells), virus-infected cells, and tumor cells.

  • Activates initiator caspase-8.

  • Execution Phase:

  • Initiator caspases (caspase-8, caspase-9) activate executioner caspases (caspase-3, caspase-6).

  • Executioner caspases activate DNase (fragmenting nuclear DNA) and degrade cytoskeletal and nuclear matrix structures.

  • Phagocytic Removal:

  • Phagocytosis of apoptotic bodies by macrophages occurs within minutes, preventing cellular contents from eliciting inflammation.

• Dysregulated apoptosis in clinical disease:

  • Reduced apoptosis: Leads to survival of abnormal cells (Cancer, Autoimmune diseases).

  • Follicular Lymphoma: Chromosomal translocation $t(14;18)(q32;q21)$ causes overexpression of anti-apoptotic Bcl-2, expanding the Bcl-2/Bcl-xL pool and protecting B lymphocytes from apoptosis.

  • Increased apoptosis: Causes excessive cell loss (Neurodegenerative diseases, Ischemic injury in myocardial infarction/stroke, AIDS viral destruction).

Comparative Analysis: Apoptosis vs. Necrosis

• Feature: Definition

  • Apoptosis: Programmed and coordinated cell death, which eliminates unwanted/harmful cells or removes cells damaged beyond repair.

  • Necrosis: Spectrum of morphologic changes that follow cell death in living tissue, largely resulting from the progressive degradative action of enzymes on lethally injured cells.

• Feature: Causes

  • Apoptosis: May be physiological or pathological.

  • Necrosis: Always pathological (e.g., hypoxia, toxins).

• Feature: Extent of Involvement

  • Apoptosis: Single or small groups of cells.

  • Necrosis: Large groups of cells.

• Feature: Inflammation

  • Apoptosis: Absent.

  • Necrosis: Present.

• Feature: Cellular Change

  • Apoptosis: Cell shrinkage and bleb formation.

  • Necrosis: Cell swelling.

• Feature: Cell Membrane

  • Apoptosis: Intact; membrane blebbing occurs.

  • Necrosis: Disrupted.

• Feature: Nucleus

  • Apoptosis: Chromatin condensation followed by fragmentation.

  • Necrosis: Nuclear pyknosis, karyolysis, and karyorrhexis.

• Feature: Lysosomes / Organelles

  • Apoptosis: Intact.

  • Necrosis: Hydrolytic enzyme release due to lysosomal rupture.

• Feature: Removal of Cell

  • Apoptosis: Phagocytosis of apoptotic bodies by macrophages.

  • Necrosis: Enzymatic digestion or phagocytosis of cell debris by macrophages.

• Feature: Mechanism

  • Apoptosis: Genetically coordinated.

  • Necrosis: Result of ATP depletion, free radical damage, mitochondrial damage.

• Feature: Electrophoretic DNA Pattern

  • Apoptosis: Agarose gel electrophoresis shows a stepladder DNA pattern.

  • Necrosis: Diffuse DNA pattern.

Cellular Adaptations to Injury

• Regulation: Adaptive changes are mediated through receptor binding, signal transduction, gene transcription, or protein synthesis.

• Atrophy:

  • Definition: Shrinkage in cell size by loss of cellular substance, leading to organ atrophy if widespread.

  • Mechanisms: Decreased protein synthesis, increased protein degradation, and presence of autophagic vacuoles containing residual bodies like lipofuscin.

  • Physiological Atrophy: Early development (notochord, thyroglossal duct) and post-partum uterine involution.

  • Pathological Atrophy:

  • Disuse atrophy: Immobilization or prolonged functional inactivity.

  • Denervation atrophy: Loss of motor nerve supply (e.g., poliomyelitis, motor neuron disease).

  • Ischaemic atrophy: Diminished blood supply (e.g., atherosclerosis).

  • Nutritional atrophy: Protein-calorie malnutrition (marasmus, cancer cachexia) where skeletal muscle is used as an energy source.

  • Endocrine loss atrophy: Loss of trophic hormones post-menopause affecting reproductive organs.

  • Senile atrophy: Aging-associated loss of permanent cells (brain, heart, testes).

  • Pressure atrophy: Increased pressure leading to tissue loss (e.g., renal parenchyma in hydronephrosis).

• Hypertrophy:

  • Definition: Increase in cell size resulting in increased organ size, driven by increased workload or hormonal stimulation.

  • Involves changes in cell phenotype; has a structural/functional ceiling beyond which degeneration and organ failure occur.

  • Physiological Hypertrophy: Hormone-driven growth (pregnant uterus, lactating breast).

  • Pathological Hypertrophy: Left ventricular hypertrophy in systemic hypertension or aortic valve stenosis; compensatory hypertrophy following destruction or resection of paired/adjacent tissue.

• Hyperplasia:

  • Definition: Increase in the number of indigenous cells in an organ or tissue; predisposing factor for neoplasia.

  • Physiologic Hyperplasia:

  • Hormonal: Proliferation of breast and uterine epithelium during puberty, pregnancy, and lactation.

  • Compensatory: Tissue mass regeneration following damage or partial resection (e.g., liver regeneration after partial hepatectomy).

  • Pathologic Hyperplasia: Excessive hormone or growth factor activity (e.g., endometrial hyperplasia from estrogen/progesterone imbalance; benign nodular prostatic hyperplasia / BPH due to androgen excess).

• Metaplasia:

  • Definition: Reversible change in which one adult cell type (epithelial or mesenchymal) is replaced by another adult cell type better suited to tolerate abnormal environments.

  • Consequences: Results in loss of normal protective functions; persistent metaplastic signals often lead to neoplasia.

  • Examples:

  • Columnar to Squamous Metaplasia: Respiratory tract in chronic cigarette smokers or Vitamin A deficiency; excretory ducts of salivary glands, pancreas, and gallbladder with calculi; chronic cervical infections.

  • Connective Tissue Metaplasia: Formation of bone, cartilage, or fat in non-mesenchymal tissues (e.g., myositis ossificans forming bone in muscle post-fracture).

• Dysplasia:

  • Definition: Disordered cellular development characterized by architectural disorientation (loss of relative cell orientation) and cellular pleomorphism (lack of uniformity).

  • Morphological features: Accelerated cell proliferation (increased mitoses), nuclear hyperchromasia, nuclear pleomorphism, and increased nuclear-to-cytoplasmic ratio.

  • Etiology: Diverse physical, chemical, or biological cellular insults; mainly affects epithelial tissues.

  • Natural history: Reversible in early stages; severe dysplasia progresses to carcinoma in situ and invasive carcinoma.

Comparative Analysis: Metaplasia vs. Dysplasia

• Feature: Definition

  • Metaplasia: Replacement of one adult epithelial or mesenchymal cell type by another.

  • Dysplasia: Disordered cellular development characterized by loss of cell orientation and lack of cell uniformity.

• Feature: Tissue Types

  • Metaplasia: Epithelial (squamous, columnar) and Mesenchymal (osseous, cartilaginous).

  • Dysplasia: Epithelial tissues only.

• Feature: Cellular Pleomorphism

  • Metaplasia: Mature cellular development without cellular pleomorphism.

  • Dysplasia: Disordered development with aberrant/delayed maturation; cellular pleomorphism present.

• Feature: Natural History

  • Metaplasia: Reversible upon withdrawal of inciting stimulus.

  • Dysplasia: May regress upon stimulus removal, or progress to higher-grade dysplasia and carcinoma in situ.

Subcellular Responses to Cell Injury

• Formation of autophagic vacuoles.

• Induction or hypertrophy of the rough endoplasmic reticulum (RER).

• Abnormal mitochondrial morphology.

• Cytoskeletal abnormalities.

Pathologic Calcification

• Dystrophic Calcification:

  • Definition: Abnormal deposition of calcium phosphate salts in dead or dying tissues.

  • Pathophysiology: Occurs despite normal systemic calcium metabolism and normal serum calcium levels.

  • Clinical involvement: Major component in the pathogenesis of atherosclerosis and valvular heart disease.

• Metastatic Calcification:

  • Definition: Deposition of calcium salts in normal living tissues as a consequence of hypercalcemia.

  • Etiology:

  • Increased parathyroid hormone (PTH) secretion leading to bone resorption.

  • Bone destruction (e.g., secondary to tumors).

  • Vitamin D disorders (intoxication, Sarcoidosis, Williams syndrome).

  • Renal failure associated with secondary hyperparathyroidism ($2^\text{o} \rightarrow \text{PTH}$ or $2^\text{o} \nearrow \text{PTH}$).

Comparative Analysis: Reversible vs. Irreversible Cell Injury

• Feature: Definition

  • Reversible injury: Structural and functional changes revert to normal upon removal of the injurious stimulus.

  • Irreversible injury: Structural and functional changes cannot be reversed even after removal of the stimulus.

• Feature: Cell Membrane

  • Reversible: Blebbing, blunting, and distortion present; membrane defects absent.

  • Irreversible: Prominent blebbing and blunting present; cellular membrane defects present.

• Feature: Endoplasmic Reticulum

  • Reversible: Shows swelling only.

  • Irreversible: Shows severe swelling and lysis.

• Feature: Ribosomes

  • Reversible: Dispersed from endoplasmic reticulum.

  • Irreversible: Dispersed and destroyed.

• Feature: Lysosomes

  • Reversible: Autophagy of damaged organelles by lysosomes; no lysosomal rupture.

  • Irreversible: Rupture of lysosomes with release of enzymes causing autolysis.

• Feature: Mitochondria

  • Reversible: Swelling and small density accumulations present.

  • Irreversible: Marked swelling and large amorphous density accumulations present.

• Feature: Nucleus

  • Reversible: Clumping of nuclear chromatin.

  • Irreversible: Pyknosis, karyolysis, or karyorrhexis.

• Feature: Calcification

  • Reversible: Absent.

  • Irreversible: Dystrophic calcification may be present.