Chapter 2
Introduction
Cell injury is the foundation of all disease processes. When cells are stressed beyond their ability to adapt, they may undergo injury, which can be reversible or irreversible. Understanding the mechanisms, morphology, and outcomes of cell injury is essential for comprehending pathologic processes across all organ systems.
This chapter explores how cells respond to injurious stimuli, the biochemical and morphologic changes that occur during this process, and the ultimate outcomes—adaptation, reversible injury, or cell death. We will also examine the different types of cell death and their significance in various disease states.
Causes of Cell Injury
Cells can be injured by a wide variety of stimuli, which can be broadly categorized as follows:
Hypoxia and Ischemia
Hypoxia (reduced oxygen supply) is the most common cause of cell injury and can result from:
Ischemia: Reduced blood flow due to arterial narrowing or obstruction
Cardiopulmonary failure: Decreased oxygen delivery despite adequate blood flow
Anemia: Reduced oxygen-carrying capacity of blood
Carbon monoxide poisoning: Interference with oxygen transport
Hypoxia rapidly affects aerobic respiration and ATP production, leading to a cascade of cellular dysfunction.
Physical Agents
Physical forms of energy can directly damage cells:
Mechanical trauma: Crushing injuries, blunt force, lacerations
Thermal injury: Burns (heat) or frostbite (cold)
Radiation: Ionizing radiation (X-rays, gamma rays) or non-ionizing radiation (UV light)
Electric shock: Current-induced damage
Pressure changes: Decompression injury, barotrauma
Chemical Agents and Drugs
Numerous chemicals can cause cell injury through various mechanisms:
Poisons: Carbon monoxide, cyanide, arsenic, mercury
Environmental pollutants: Air pollutants, industrial chemicals
Therapeutic drugs: Acetaminophen, chemotherapeutic agents
Alcohol: Direct hepatotoxicity and metabolic effects
Recreational drugs: Cocaine, heroin, methamphetamine
Infectious Agents
Microorganisms can injure cells through:
Direct cytopathic effects: Viral lysis of cells
Toxin production: Bacterial exotoxins and endotoxins
Inflammatory response: Host immune reaction to infection
Metabolic competition: Nutrient depletion by microorganisms
Immunologic Reactions
The immune system can cause cell injury through:
Hypersensitivity reactions: Types I-IV
Autoimmune disorders: Systemic lupus erythematosus, rheumatoid arthritis
Transplant rejection: Cell-mediated and antibody-mediated damage
Genetic Factors
Genetic abnormalities can lead to cell injury through:
Inborn errors of metabolism: Lysosomal storage diseases, glycogen storage diseases
Chromosomal disorders: Down syndrome, Turner syndrome
Single-gene disorders: Cystic fibrosis, sickle cell anemia
Nutritional Imbalances
Both deficiency and excess of nutrients can cause cell injury:
Protein-calorie malnutrition: Marasmus, kwashiorkor
Vitamin deficiencies: Scurvy (vitamin C), beriberi (thiamine)
Obesity: Metabolic stress, lipotoxicity
Malabsorption: Celiac disease, inflammatory bowel disease
Mechanisms of Cell Injury
Regardless of the initial cause, cell injury involves several common biochemical pathways:
ATP Depletion
ATP (adenosine triphosphate) is essential for maintaining cellular homeostasis. Depletion of ATP leads to:
Failure of sodium-potassium ATPase pump → sodium influx → cell swelling
Detachment of ribosomes from endoplasmic reticulum → reduced protein synthesis
Anaerobic glycolysis → lactic acid production → decreased intracellular pH
Reduced calcium sequestration → increased cytosolic calcium
Mitochondrial Damage
Mitochondria are both targets and sources of cell injury:
Mitochondrial permeability transition (MPT) → release of cytochrome c → apoptosis
Reduced oxidative phosphorylation → decreased ATP production
Increased production of reactive oxygen species (ROS)
Calcium overload → mitochondrial swelling and rupture
Membrane Damage
Cell membranes are vulnerable to various forms of injury:
Lipid peroxidation by free radicals → membrane disruption
Cytoskeletal damage → membrane blebbing
Phospholipase activation → phospholipid degradation
Loss of membrane phospholipid asymmetry → exposure of phosphatidylserine
Calcium Homeostasis Disruption
Increased cytosolic calcium is a final common pathway in cell injury:
Activation of phospholipases → membrane damage
Activation of proteases → protein degradation
Activation of endonucleases → DNA fragmentation
Mitochondrial damage → further ATP depletion
Reactive Oxygen Species (ROS)
Free radicals and other reactive oxygen species cause cell injury through:
Lipid peroxidation of membranes
Oxidative modification of proteins → enzyme inactivation
DNA damage → mutations, strand breaks
Activation of inflammatory mediators
Defects in Membrane Permeability
Altered membrane permeability leads to:
Influx of calcium and sodium → cell swelling
Efflux of potassium → altered membrane potential
Leakage of cellular enzymes → diagnostic markers of cell injury
Entry of normally excluded molecules → further cell damage
Reversible Cell Injury
When injury is mild to moderate and the stimulus is removed in time, cells can recover through a process called reversible cell injury.
Morphologic Changes in Reversible Injury
Cellular Swelling (Hydropic Change)
Earliest manifestation of almost all forms of injury
Results from failure of ATP-dependent ion pumps
Microscopic appearance: pale, swollen cells with small clear vacuoles
Particularly evident in renal tubular epithelium, hepatocytes
Fatty Change
Accumulation of triglycerides within cells
Most commonly seen in liver (steatosis), heart, kidney
Microscopic appearance: clear vacuoles displacing cytoplasm and nucleus
Special stains (Oil Red O) highlight lipid content
Causes: alcohol, diabetes, obesity, toxins, hypoxia
Biochemical Changes in Reversible Injury
Decreased ATP production
Cellular swelling due to sodium and water influx
Detachment of ribosomes from rough endoplasmic reticulum
Mild mitochondrial swelling
Plasma membrane blebbing
Myelin figure formation
Ultrastructural Changes in Reversible Injury
Plasma membrane alterations: blebbing, loss of microvilli
Mitochondrial changes: swelling, appearance of amorphous densities
Dilation of endoplasmic reticulum
Disaggregation of polyribosomes
Cytoskeletal alterations
Irreversible Cell Injury and Cell Death
When injury is severe or prolonged, cells pass a "point of no return" and die. The two main types of cell death are necrosis and apoptosis.
Necrosis
Necrosis is a pathologic form of cell death resulting from acute cellular injury. It is characterized by:
Morphologic Features of Necrosis
Cell swelling and rupture
Denaturation and coagulation of cytoplasmic proteins
Breakdown of organelles
Nuclear changes: pyknosis (condensation), karyorrhexis (fragmentation), karyolysis (dissolution)
Intense eosinophilic (pink) cytoplasmic staining due to protein denaturation
Loss of cellular detail
Biochemical Features of Necrosis
Massive calcium influx
Rapid ATP depletion
Extensive membrane damage
Random DNA degradation
Release of cellular contents → inflammatory response
Lysosomal enzyme leakage → digestion of cellular components
Patterns of Necrosis
Coagulative Necrosis
Most common pattern
Preservation of tissue architecture initially
Characteristic of hypoxic death in all tissues except brain
Example: Myocardial infarction
Liquefactive Necrosis
Digestion of dead cells by hydrolytic enzymes
Characteristic of brain infarcts
Also seen in bacterial infections (abscess formation)
Results in liquefied debris
Caseous Necrosis
Combination of coagulative and liquefactive necrosis
Characteristic of tuberculosis
Gross appearance: soft, friable, cheese-like material
Microscopic appearance: amorphous eosinophilic material with loss of cellular detail
Fat Necrosis
Enzymatic digestion of fat by lipases
Seen in pancreatic inflammation (acute pancreatitis)
Gross appearance: chalky white areas
Microscopic appearance: "ghost" outlines of fat cells, calcium soap formation
Fibrinoid Necrosis
Immune-mediated vascular damage
Characteristic of malignant hypertension, immune complex vasculitis
Microscopic appearance: bright eosinophilic material in vessel walls
Apoptosis
Apoptosis is a programmed, energy-dependent form of cell death that eliminates cells without eliciting inflammation.
Morphologic Features of Apoptosis
Cell shrinkage
Chromatin condensation and margination
Nuclear fragmentation
Membrane blebbing
Formation of apoptotic bodies
Phagocytosis of apoptotic bodies by adjacent cells or macrophages
Absence of inflammation
Biochemical Features of Apoptosis
Activation of caspases (cysteine proteases)
Controlled proteolysis of cellular components
Internucleosomal DNA cleavage → "ladder pattern" on gel electrophoresis
Externalization of phosphatidylserine → recognition by phagocytes
Preservation of membrane integrity until late stages
ATP-dependent process
Pathways of Apoptosis
Extrinsic (Death Receptor) Pathway
Initiated by binding of ligands to death receptors (Fas, TNF receptor)
Activation of initiator caspase-8
Subsequent activation of executioner caspases (3, 6, 7)
Examples: Immune-mediated cell killing, pathologic cell death in viral hepatitis
Intrinsic (Mitochondrial) Pathway
Triggered by intracellular stress (DNA damage, oxidative stress)
Regulated by Bcl-2 family proteins (pro-apoptotic: Bax, Bak; anti-apoptotic: Bcl-2, Bcl-XL)
Release of cytochrome c from mitochondria
Formation of apoptosome
Activation of caspase-9 → executioner caspases
Examples: Radiation-induced cell death, chemotherapy-induced apoptosis
Physiologic and Pathologic Roles of Apoptosis
Physiologic Roles:
Embryonic development and tissue remodeling
Hormone-dependent involution (endometrium, breast)
Deletion of autoreactive lymphocytes
Elimination of infected cells
Turnover of senescent cells
Pathologic Roles:
Insufficient apoptosis: Cancer, autoimmune disorders
Excessive apoptosis: Neurodegenerative diseases, AIDS, ischemic injury
Autophagy
Autophagy is a cellular process that can lead to cell survival or death depending on context.
Self-digestion of cellular components through lysosomal mechanisms
Formation of autophagosomes containing cytoplasmic material
Fusion with lysosomes → degradation of contents
Adaptive response to nutrient deprivation
May promote survival or lead to cell death ("autophagic cell death")
Implicated in neurodegenerative diseases, cancer, aging
Necroptosis
Necroptosis is a regulated form of necrosis with features of both apoptosis and necrosis.
Programmed necrosis mediated by receptor-interacting protein kinases (RIPK1, RIPK3)
Morphologically resembles necrosis
Molecularly regulated like apoptosis
Occurs when apoptosis is inhibited
Associated with inflammatory response
Implicated in ischemic injury, neurodegenerative diseases
Subcellular Responses to Injury
Nuclear Changes
Pyknosis: Nuclear shrinkage and increased basophilia
Karyorrhexis: Nuclear fragmentation
Karyolysis: Dissolution of nucleus
Intranuclear inclusions: Viral infections (CMV, herpes)
Intranuclear vacuoles: Fatty liver disease
Cytoplasmic Changes
Fatty change: Accumulation of triglycerides
Hyaline change: Eosinophilic glassy appearance
Vacuolization: Formation of membrane-bound spaces
Inclusions: Storage diseases, viral infections
Hydropic change: Cellular swelling due to water influx
Protein Misfolding
Accumulation of misfolded proteins → ER stress
Unfolded protein response (UPR) activation
If prolonged → cell death
Examples: Neurodegenerative diseases (Alzheimer's, Parkinson's)
Cellular Adaptations
Before reaching the stage of injury, cells may adapt to stress through various mechanisms:
Atrophy
Decrease in cell size and organ size
Causes: Reduced workload, decreased blood supply, loss of innervation
Microscopic features: Smaller cells, increased autophagic vacuoles
Examples: Skeletal muscle atrophy in disuse, brain atrophy in aging
Hypertrophy
Increase in cell size without cell division
Causes: Increased workload, hormonal stimulation
Microscopic features: Enlarged cells with increased organelles
Examples: Cardiac hypertrophy in hypertension, uterine hypertrophy in pregnancy
Hyperplasia
Increase in cell number due to proliferation
Causes: Hormonal stimulation, compensatory mechanisms
Microscopic features: Increased number of normal-appearing cells
Examples: Endometrial hyperplasia, compensatory liver hyperplasia
Metaplasia
Replacement of one differentiated cell type by another
Adaptive response to chronic irritation
Microscopic features: Presence of cell type not normally found at that site
Examples: Squamous metaplasia of respiratory epithelium in smokers, Barrett's esophagus
Intracellular Accumulations
Cells may accumulate various substances when normal metabolism is disturbed:
Lipids
Triglycerides: Fatty liver disease, atherosclerosis
Cholesterol: Atherosclerosis, xanthomas
Phospholipids: Niemann-Pick disease
Proteins
α1-Antitrypsin: Liver disease
Immunoglobulins: Plasma cell dyscrasias
Neurofibrillary tangles: Alzheimer's disease
Carbohydrates
Glycogen: Glycogen storage diseases
Mucopolysaccharides: Mucopolysaccharidoses
Pigments
Endogenous:
Lipofuscin: "Wear and tear" pigment, aging
Melanin: Skin, melanocytic lesions
Hemosiderin: Hemochromatosis, local hemorrhage
Bilirubin: Jaundice
Exogenous:
Carbon: Anthracosis (coal dust)
Tattoo pigments
Heavy metals: Lead, silver
Pathologic Calcification
Abnormal deposition of calcium salts in tissues:
Dystrophic Calcification
Occurs in damaged or necrotic tissue
Normal serum calcium levels
Examples: Atherosclerotic plaques, tuberculosis, damaged heart valves
Metastatic Calcification
Occurs in normal tissues
Elevated serum calcium levels
Causes: Hyperparathyroidism, renal failure, vitamin D excess, malignancy
Common sites: Kidneys, lungs, gastric mucosa
Cellular Aging
Aging at the cellular level involves:
Telomere shortening
Accumulation of DNA damage
Mitochondrial dysfunction
Oxidative stress
Impaired protein homeostasis
Altered intercellular communication
Cellular senescence
Clinical Correlations
Biomarkers of Cell Injury
Cellular enzymes released upon injury serve as diagnostic markers:
Cardiac Troponins (I and T): Highly specific for myocardial injury
Creatine Kinase (CK-MB): Elevated in myocardial infarction
Aspartate Aminotransferase (AST): Released in liver and cardiac injury
Alanine Aminotransferase (ALT): More specific for liver injury
Amylase and Lipase: Elevated in pancreatic injury
Lactate Dehydrogenase (LDH): Nonspecific marker of cell injury
Therapeutic Implications
Understanding cell injury mechanisms informs therapeutic strategies:
Antioxidants: May limit free radical-mediated injury
Calcium Channel Blockers: Reduce calcium-mediated injury
Anti-apoptotic Agents: Potential for treating degenerative diseases
Pro-apoptotic Agents: Basis for many cancer therapies
Caspase Inhibitors: Experimental therapy for ischemic injury
Clinical Examples
Myocardial Infarction
Ischemic injury → coagulative necrosis
Release of troponins, CK-MB → diagnostic markers
Border zone: mixture of reversible and irreversible injury
Therapeutic window for reperfusion therapy
Viral Hepatitis
Direct cytopathic effect + immune-mediated injury
Release of ALT, AST → diagnostic markers
Apoptosis of infected hepatocytes
Potential for regeneration vs. progression to fibrosis
Acute Tubular Necrosis
Ischemic or toxic injury to renal tubules
Cellular swelling → tubular obstruction
Sloughing of tubular cells → urinary casts
Potential for regeneration and recovery
Neurodegenerative Diseases
Accumulation of misfolded proteins
Chronic ER stress → apoptosis
Selective vulnerability of specific neuronal populations
Progressive, irreversible cell loss
Summary of Key Concepts
Cell injury results from various stimuli and involves common pathways including ATP depletion, calcium dysregulation, and free radical damage.
Reversible injury is characterized by cellular swelling and fatty change, while irreversible injury leads to cell death.
Necrosis is a pathologic form of cell death characterized by cell swelling, membrane rupture, and inflammation.
Apoptosis is a programmed form of cell death characterized by cell shrinkage, nuclear fragmentation, and absence of inflammation.
Different patterns of necrosis (coagulative, liquefactive, caseous, fat, fibrinoid) have distinct morphologic features and disease associations.
Cellular adaptations (atrophy, hypertrophy, hyperplasia, metaplasia) represent responses to stress that precede injury.
Intracellular accumulations and pathologic calcification reflect disturbances in normal metabolism and tissue damage.
Biomarkers of cell injury serve as important diagnostic tools in clinical medicine.
Practice Questions
A 62-year-old man presents with crushing chest pain radiating to the left arm. Cardiac troponin levels are elevated. Which pattern of necrosis would most likely be observed in the affected myocardium? A. Liquefactive necrosis B. Caseous necrosis C. Coagulative necrosis D. Fat necrosis E. Fibrinoid necrosis
A pathologist observes cells with condensed, fragmented nuclei and intact cell membranes forming small, membrane-bound bodies that are being phagocytosed by neighboring cells. No inflammatory response is present. Which process is being observed? A. Necrosis B. Apoptosis C. Autophagy D. Hydropic degeneration E. Metaplasia
Which of the following is a characteristic feature of reversible cell injury but not irreversible cell injury? A. Plasma membrane rupture B. Extensive mitochondrial damage C. Cellular swelling D. Nuclear pyknosis E. Karyolysis
A 45-year-old woman with a history of alcohol abuse presents with right upper quadrant pain. Liver biopsy shows hepatocytes with large, clear cytoplasmic vacuoles that displace the nucleus to the periphery. Which of the following best describes this change? A. Hydropic degeneration B. Fatty change C. Hyaline change D. Glycogen accumulation E. Metaplasia
Which of the following is the primary mechanism by which hypoxia leads to cell injury? A. Direct DNA damage B. Protein denaturation C. ATP depletion D. Lipid peroxidation E. Calcium influx
Answers:
C. Coagulative necrosis is the typical pattern seen in myocardial infarction, characterized by preservation of cellular outlines with loss of nuclei and intensely eosinophilic cytoplasm.
B. Apoptosis is characterized by nuclear condensation and fragmentation, formation of membrane-bound apoptotic bodies, phagocytosis by neighboring cells, and absence of inflammation.
C. Cellular swelling is a characteristic of reversible cell injury. Plasma membrane rupture, extensive mitochondrial damage, nuclear pyknosis, and karyolysis are features of irreversible injury.
B. Fatty change (steatosis) is characterized by accumulation of triglycerides within hepatocytes, appearing as clear vacuoles that displace the nucleus. This is commonly seen in alcohol abuse.
C. Hypoxia primarily causes cell injury through ATP depletion, which leads to failure of energy-dependent cellular processes, including membrane ion pumps, resulting in subsequent changes like calcium influx.