Cell Injury, Adaptation, and Death 2024 PDF

Pathology Cell Injury, Adaptation, and Death Catherine M. Flaitz, DDS, MS Professor, Oral & Maxillofacial Pathology [email protected] May 2024 Learning Objectives Know the general causes of cell and tissue injury. Understand the mechanism and components of cellular injury. Describe how...

Pathology Cell Injury, Adaptation, and Death Catherine M. Flaitz, DDS, MS Professor, Oral & Maxillofacial Pathology [email protected] May 2024 Learning Objectives Know the general causes of cell and tissue injury. Understand the mechanism and components of cellular injury. Describe how cellular injury translates into a microscopic appearance. Know about the different cellular and tissue adaptations to injury. Discuss the difference between necrosis and apoptosis. Describe all the different patterns of necrosis. Describe the mechanism and morphologic features of apoptosis. Provide examples of cellular accumulations and effect on tissues Discuss the mechanism for cellular aging Etiology & Pathogenesis Etiology represents the why Pathogenesis represents the how Together, they are essential for understanding disease, providing rational treatment and developing preventive measures Provide the scientific foundation for the practice of health care Causes of Cell/Tissue Injury Important: Cell injury is the basis of all disease Hypoxia & Ischemia: O2 deficiency & reduced blood flow and supply of nutrients – common Toxins: Environmental, therapeutic and illicit drugs, cig smoke, ethanol, pollutants, insecticides, carbon monoxide Infectious agents: Viruses, bacteria, fungi, parasites → release toxins and elicit harmful immune response Immunologic reactions: Allergies, autoimmune, excessive response to microbes → beneficial and destructive Genetic: Chromosomal (Down syndrome), gene-specific disease, mutations play role in cancer Nutritional: Protein, calorie, vitamin deficiency and excess – diabetes, obesity, atherosclerosis, caries Physical agents: Trauma, radiation, electric shock, temperature and atmospheric pressure changes Aging: Cellular senescence – diminished ability to respond to stress Steps in the Development of Disease N.B. Cell injury is the basis for all disease Stages of Cellular Response to Stress and Injurious Stimuli Reversible injury is the stage of cell injury at which the function and morphology of injured cells can return to normal function and morphology, if the damaging stimulus is removed Reversible Cell Injury 2 main morphologic correlates Cellular swelling – increase permeability – also referred to hydropic change Fatty change – lipid vacuoles in cytoplasm Cellular Swelling: results in pallor, increase turgor (pressure exerted by cellular fluid content & extracellular fluid), increase organ weight Diagnosis: Linea alba, and cheek-biting keratosis Micro findings: Shaggy hyperkeratosis, acanthosis, and intracellular edema or spongiosis Hydropic change or vacuolar degeneration: small clear vacuoles in cytoplasm that represent pinched off segments of the ER Fatty Change: Occurs in organs involved in lipid metabolism Liver is the primary organ Micro: See lipid vacuoles in cytoplasm that are also clear Reversible & Irreversible Cell Injury and Necrosis If injurious stimulus is not removed in time, necrosis occurs Cell Death and Apoptosis Types: physiologic or pathologic If pathologic, apoptosis eliminates cells with irreparable DNA damage or excessive misfolded proteins Mechanism of Cell Injury: Vulnerable Systems Hypoxia & Ischemia Ischemia-reperfusion injury Oxidative stress Protein misfolding DNA damage Inflammation Infections ATP (adenosine triphosphate) ROS (Reactive oxygen species) Mechanism of Cell Injury: Vulnerable Systems Maintenance of integrity of cell membranes Aerobic respiration (ATP production) by mitochondria Synthesis of structural proteins and enzymes (ER) Preservation of genetic apparatus (DNA integrity) Summary: Mechanism of Cell Injury ▪ Different initiating events cause cell injury and death. ▪ Mitochondrial damage and increased permeability of cellular membranes are often late events in cell injury and necrosis from different causes. ▪ Oxidative stress refers to accumulation of ROS, which can damage cellular lipids, proteins, and DNA - associated with numerous initiating causes. ▪ ER stress: Protein misfolding depletes essential proteins and, if the misfolded proteins accumulate within cells, triggers apoptosis. ▪ DNA damage, e.g., radiation, can induce apoptosis if it is not repaired. ▪ Hypoxia & ischemia lead to ATP depletion and failure of energy-dependent functions, resulting in reversible injury and, if not corrected, necrosis. ▪ In ischemia-reperfusion injury, restoration of blood flow to an ischemic tissue exacerbates damage by increasing production of ROS and by increasing inflammation. CONCEPTS - CELL DEATH Necrosis Adult complains of a painful swelling of gingiva that periodically drains. Severe disturbance causes rapid, uncontrolled form of death, accidental cell death Primary cause is injury Not regulated by specific signals or biochemical mechanisms Cellular membranes fall apart Cellular enzymes leak out and digest cell Elicits inflammation Cell Membranewhy so easily injured? ▪Membrane faces the external environment: sustains “trauma”, extracellular oxidants, proteases, etc. ▪Requires a constant supply of ATP for normal function (ion pumps). ▪Lipid molecules in the membrane are easily oxidized and support an oxidative chain reaction called lipid peroxidation. Cellular Stages of Necrosis: Important Definitions Cellular swelling in early stages of necrosis is associated with swelling of the mitochondria and ER. Cytoplasmic RNA is removed, resulting in more intensely eosinophilic cytoplasm. Nucleolus is lost, and nucleus condenses, shrinks, and becomes intensely basophilic in a process termed pyknosis. The pyknotic nucleus fragments in a process termed karyorrhexis. The nucleus undergoes complete dissolution in a process known as karyolysis. The remaining bag of denatured protein (former cell) is cleared by reticuloendothelial system. The process of dissolution of dead cells by intrinsic and extrinsic hydrolases is “autolysis”. Illustration of Cellular Necrosis Reversible Cell Injury and Necrosis of Renal Cells Normal Reversible Necrosis Patterns of Necrosis: Important Definitions Coagulative necrosis: architecture of dead tissue preserved (days) Liquefactive necrosis: digestion of dead cells causes liquid viscous mass Gangrenous necrosis: not specific pattern of cell death, death of tissue due to insufficient blood supply Caseous necrosis: white/cheese-like appearance of dead cell region (observed with tuberculous infection) Fibrinoid necrosis: usually seen in immune reactions within blood vessels Fat necrosis: not really necrotic pattern, focal areas of fat destruction Coagulative Necrosis of the Kidney Architecture of dead tissue preserved (days) Necrotizing Gingivitis/Periodontitis Severe, painful, inflammatory periodontal disease caused by proliferation of oral biofilm and bacteria associated with diminished host defense. Coagulative necrosis Case History ID: 25YO male CC: “Hole in the roof of mouth” Med Hx: E-cig daily; social drinker Duration: 1-month swelling following an upper respiratory infection S/S: Deep ulcer with thick pseudomembrane; mildly tender Large ulcer of posterior hard palate Histopathology Normal Disease Necrotizing Sialometaplasia Destructive inflammatory condition of the salivary glands Cause: Ischemia local infarction due to trauma Location: Palate Necrosis of acinar structures – coagulation necrosis – architecture maintained, mucin, inflammation Squamous metaplasia of ducts Spontaneous healing Mimics a malignancy Liquefactive Necrosis of Brain Digestion of dead cells causes liquid viscous mass Liquefactive Necrosis ✓Digestion of dead cells causes liquid viscous mass ✓Represents a parulis due to nonvital premolar Adult complains of a painful swelling of gingiva that periodically drains. Liquefactive Necrosis – Abscess on skin of arm Digestion of dead cells causes liquid viscous mass Caseous Necrosis of the Lung ✓ White/cheese-like appearance of dead cell region ✓ Associated with tuberculosis Fibrinoid Necrosis in an Artery Usually seen in immune reactions within blood vessels Fibrinoid Necrosis in Artery Usually seen in immune reactions within blood vessels Behcet syndrome ✓Systemic vasculitis ✓Oral ulcer ✓Genital ulcer ✓Skin lesions ✓Ocular lesions Not really necrotic pattern; focal areas of fat destruction Fat Necrosis in Mesentery Case History: ID: 3YO male – recent mouth trauma Nontender yellowish mass developed rapidly after toy was removed from the buccal mucosa Herniated Buccal Fat Pad Results is fat necrosis – focal areas of fat destruction Apoptosis Greek for “falling off”, as in leaves on a tree Programmed cell death or cellular suicide (tightly regulated) Distinct from necrosis: No significant inflammatory reaction No loss of cell membrane integrity or leakage of cellular contents Can coexist with necrosis APOPTOSIS: MAINTAINER OF HOMEOSTASIS Normal cell turnover – cells with short half-life – tissue involution due to loss of growth factor stimulation or hormonal changes (endometrium during menstrual cycle) Embryogenesis: cell elimination due to loss of growth factor signaling Immune function – decline in leukocytes at end of inflammation – elimination of harmful self-reactive lymphocytes Pathologic Apoptosis DNA damage such as radiation treatment or cytotoxic drugs – activates proapoptotic proteins Accumulation of misfolded proteins – activates proapoptotic proteins and activation of caspases (cysteine proteases) Infections, esp viral infections such as adenoviruses and herpesviruses, EBV & HHV-8 Activation of proapoptotic proteins or caspases by viral proteins Killing of infected cells by cytotoxic T lymphocytes (CTLs), which activate Oral mucositis from chemotherapy caspases APOPTOSIS AND DISEASE Excessive Apoptosis Examples: ✓ AIDS ✓ Ischemia ✓ Neurodegenerative disease ✓ Toxin-induced liver injury AIDS and wasting disease APOPTOSIS AND DISEASE Inhibition of Apoptosis Cancer - e.g. follicular lymphoma, carcinomas of breast, prostate and ovaries Lymphoma of submandibular lymph nodes Morphological Changes in Apoptosis Cell Shrinkage Chromatin condensation (most characteristic feature) Cytoplasmic blebs Apoptotic or acidophilic bodies Phagocytosis of apoptotic bodies Example of Apoptosis in Intestinal Epithelium Two Pathways for Apoptosis Autophagy: “Self-eating” refers to lysosomal digestions of the cell’s own components Autophagy is triggered by nutrient deprivation Characterized by degradation & recycling of cellular contents for energy during stress Can trigger apoptosis, if the stress is not relieved Features of Necrosis and Apoptosis Review: Patterns of Cell Injury & Cell Death ▪ Causes of cell injury: ischemia, toxins, infections, immunologic reactions, genetic, nutritional imbalances, physical agents (e.g., trauma, burns), aging ▪ Reversible cell injury: cell swelling, fatty change, plasma membrane blebbing and loss of microvilli, mitochondrial swelling, dilation of the ER, eosinophilia (due to decreased cytoplasmic RNA), myelin figures ▪ Necrosis: eosinophilia; nuclear shrinkage, fragmentation, and dissolution; breakdown of plasma membrane and organellar membranes; leakage and enzymatic digestion of cellular contents; elicits inflammation ▪ Morphologic types of tissue necrosis: coagulative, liquefactive, gangrenous, caseous, fat, and fibrinoid. Review: Patterns of Cell Injury & Cell Death ▪ Apoptosis: regulated mechanism of cell death that eliminates unnecessary and irreparably damaged cells, without injurious host reaction; characterized by enzymatic degradation of proteins and DNA, initiated by caspases, and by recognition and removal of dead cells by phagocytes ▪ Two major pathways of apoptosis: 1. Mitochondrial (intrinsic) pathway is triggered by loss of survival signals, DNA damage, and accumulation of misfolded proteins (ER stress) ▪ 2.Death receptor (extrinsic) pathway is responsible for elimination of selfreactive lymphocytes and damage by cytotoxic T lymphocytes; initiated by engagement of death receptors (TNF receptor family) with ligands on adjacent cells. ▪ Autophagy is triggered by nutrient deprivation; characterized by degradation and recycling of cellular contents to provide energy during stress; can trigger apoptosis if the stress is not relieved. CONCEPTS IN CHRONIC CELL INJURY Cells undergo adaptive changes due to persistent (chronic) stress/injury Morphologic changes seldom specific to the type of persistent (chronic) stress Similar responses at the cell level can produce different morphologic changes in different organs. Cellular Adaptation to Stress Generally reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment. 2 types include: Physiologic: represents responses of cells to normal stimulation Hormones or endogenous chemical mediators (breast enlargement) Demands of mechanical stress (↑ muscle mass) Pathologic: responses that modulate their structure & function and escape cell injury (epithelial changes from smoking) CAUSES OF CHRONIC CELL INJURY Ischemia, hormones, infections, chemicals/drugs, trauma, genetics, etc. Strength of the insult may be minimal Duration of stress is prolonged as compared to acute cell injury CELLULAR ADAPTATIONS Atrophy Hypertrophy Hyperplasia Metaplasia Types of Adaptation Hypertrophy – increase in size of cells, often resulting in increase in size of organ (eg. heart). Atrophy - decreased cell size and number resulting in reduced size of organ or tissue (eg. brain). Hyperplasia – increase in number or cells (eg. liver regeneration) Metaplasia – conversion of one differentiated cell type to another (eg. bronchus). If persistent, then increase risk for malignant transformation ETIOLOGIES OF HYPERTROPHY ▪ Increased functional demand ▪ Increased or imbalanced nutrition ▪ Increased hormonal stimulation Normal, Adapted, Reversibly Injured, and Dead Myocardial Cells Kumar, Vinay et al., Published January 1, 2015. Pages 31-68. © 2015. Masseter muscle: - Right is normal - Left shows hypertrophy Types of Adaptation Hypertrophy – increase in size of cells, often resulting in increase in size of organ (eg. Heart, muscles). Atrophy - decreased cell size and number resulting in reduced size of organ or tissue (eg. brain). Hyperplasia – increase in number or cells (eg. liver regeneration) Metaplasia – conversion of one differentiated cell type to another (eg. bronchus, esophagus). If persistent, then increase risk for malignant transformation ETIOLOGIES OF ATROPHY Decreased workload Loss of innervation Decreased blood supply Inadequate nutrition Decreased hormonal stimulation Aging Local pressure ETIOLOGIES OF ATROPHY Decreased workload Loss of innervation Normal Atrophic Renal atrophy Chronic ischemia ETIOLOGIES OF ATROPHY Starvation Withdrawal of estrogen stimulation Normal Breast Postmenopausal Example of Atrophy Normal Brain Atrophic Brain Atrophic Alveolar Ridges Enlargement of tongue (Macroglossia) Types of Adaptation Hypertrophy – increase in size of cells, often resulting in increase in size of organ (eg. heart). Atrophy - decreased cell size and number resulting in reduced size of organ or tissue (eg. brain). Hyperplasia – increase in number or cells (eg. liver regeneration) Metaplasia – conversion of one differentiated cell type to another (eg. bronchus). If persistent, then increase risk for malignant transformation HYPERPLASIA DUE TO CHRONIC IRRITATION Traumatic keratosis Hyperkeratosis & epithelial hyperplasia HYPERPLASIA DUE TO CHRONIC IRRITATION Irritation fibroma Hyperkeratosis & epithelial hyperplasia Increase on collagen fibers Types of Adaptation Hypertrophy – increase in size of cells, often resulting in increase in size of organ (eg. heart). Atrophy - decreased cell size and number resulting in reduced size of organ or tissue (eg. brain). Hyperplasia – increase in number or cells (eg. liver regeneration) Metaplasia – conversion of one differentiated cell type to another (eg. bronchus, esophagus). If persistent, then increase risk for malignant transformation Example of Metaplasia Metaplasia of columnar to squamous epithelium in a lung bronchus Summary: Cellular Adaptations to Stress ▪ Hypertrophy: increased cell and organ size, often in response to increased workload; induced by growth factors produced in response to mechanical stress or other stimuli; occurs in tissues incapable of cell division ▪ Hyperplasia: increased cell numbers in response to hormones and other growth factors; occurs in tissues whose cells are able to divide or contain abundant tissue stem cells ▪ Atrophy: decreased cell and organ size, due to decreased nutrient supply or disuse; associated with decreased synthesis of cellular building blocks and increased breakdown of cellular organelles ▪ Metaplasia: change in phenotype of differentiated cells in response to chronic irritation; cells better able to withstand the stress; may result in reduced functions or increased propensity for malignant transformation Intracellular Accumulations Abnormal amounts of substances in cytoplasm or nucleus Inadequate removal/degradation or deposition of substance Fatty change (steatosis): triglycerides in cells, e.g., fatty liver Cholesterol: phagocytic cells become overloaded with lipid, e.g., atherosclerosis Proteins: ↑ in reabsorption of protein in kidneys – nephrotic syndrome Glycogen: e.g., diabetes – beta cells in pancreas Pigments: endogenous or exogenous - Lipofuscin, melanin, hemosiderin Mechanism of Intracellular Accumulation 1. Abnormal metabolism 2. Defect in protein folding and transport 3. Lack of enzymes 4. Ingestion of soluble materials CELLULAR ACCUMULATIONS Normal constituents - H20, lipids, proteins, carbohydrate Abnormal substances - endogenous or exogenous Pigments Calcium Labial melanotic macule TRIGLYCERIDE ACCUMULATION STEATOSIS (FATTY LIVER) Normal Liver Fatty Liver Oil Red O Stain CHOLESTEROL IN VESSELS Atherosclerosis Cholesterol thrombus PROTEIN ACCUMULATION 1- Anti-trypsin deficiency genetic cause of COPD Mallory body in alcoholic hepatitis – cytokeratin intermediate filament Tau protein and amyloidbeta in Alzheimer disease Protein Accumulation Tau protein CARBOHYDRATES GLYCOGEN STORAGE DISEASE Group of inherited conditions that changes the way the body uses and stores glycogen Lack the enzymes to breakdown glycogen which then builds up in liver and muscles Develop hypoglycemia, muscle weakness, mental disability, weight gain, failure to grow Micro: Cytoplasmic glycogen in the hepatocytes Liver disease ENDOGENOUS PIGMENTS Lipofuscin granules in cardiac myocytes Hemosiderin granules in livers cells Case History ID: 64 YO male CC: Severe swelling of floor of mouth following anterior implant placement Med Hx: Hypertension controlled by hydrochlorothiazide Hematoma after placement of anterior implants Hematoma with Macrophages and Hemosiderin – Endogenous Substance ENDOGENOUS PIGMENTS Congenital melanocytic nevus Melanin pigmentation EXOGENOUS CARBON PIGMENT Anthracosis Pneumoconiosis Coal Workers Lungs EXOGENOUS PIGMENTS Amalgam Tattooing Pathologic Calcifications Common but abnormal deposition of calcium salts occurs in 2 ways Dystrophic calcification: Normal calcium metabolism but is deposited in injured or dead tissue, e.g., calcification of lymph nodes in TB Metastatic calcification: Due to hypercalcemia Increase secretion of parathyroid hormone Destruction of bone due to rapid turnover or tumors Vitamin-D related disorders Renal failure causing secondary hyperparathyroidism Caseous Necrosis of the Lung White/cheese-like appearance of dead cell region Associated with tuberculosis Calcification of anterior cervical lymph nodes from tuberculosis (see arrows) Calcification of Carotid Artery associated with Atherosclerosis in a 60 YOM (see arrows) Eagle’s Syndrome: Head & neck pain, especially jaw, throat and ears when turning head, and swallowing Elongation of stylohyoid and calcification of stylohyoid ligament Abnormal Intracellular Depositions & Calcifications ▪ Cause: Abnormal deposits of materials in cells and tissues are the result of excessive intake or defective transport or catabolism. ▪ Lipids: Fatty change or cholesterol deposition ▪ Fatty change: Accumulation of free triglycerides in cells, resulting from excessive intake or defective transport; manifestation of reversible cell injury ▪ Cholesterol deposition: Result of defective catabolism and excessive intake; in macrophages and smooth muscle cells of vessel walls in atherosclerosis Abnormal Intracellular Depositions & Calcifications ▪ Proteins: reabsorbed proteins in kidney tubules; immunoglobulins in plasma cells ▪ Glycogen: in macrophages of patients with defects in lysosomal enzymes that break down glycogen (glycogen storage diseases) ▪ Pigments: typically indigestible pigments, such as carbon, lipofuscin (breakdown product of lipid peroxidation), or hemosiderin (usually due to iron overload) ▪ Pathologic calcifications: ▪ Dystrophic calcification: deposition of calcium at sites of cell injury and necrosis ▪ Metastatic calcification: deposition of calcium in normal tissues, caused by hypercalcemia (parathyroid hormone excess) Cellular Ageing Result of progressive decline in life span and functional activity of cells Several abnormalities contribute to cell aging Accumulation of damage & mutations in DNA Replicative senescence – reduced capacity of cells to divide due to shortened telomeres Defective protein homeostasis – normal protein replaced by misfolded protein Aging is exacerbated by chronic disease, esp. prolonged inflammation, and by stress Process slowed by calories restriction and exercise Mechanism for Cellular Aging Multiple mechanisms contribute to cellular aging. Environmental modifications, such as calorie restriction, counteract aging by activating various signaling pathways and transcription factors. ROS, Reactive oxygen species; TOR, target of rapamycin. Telomeres & Ageing Signs of Aging