2024 DSUR3210 IWB Cell Injury and Cell Death PDF

School of Dentistry Faculty of Medicine & Health Illness and Well-being ( DSUR3210) Cell injury and cell death Dr Gordon Hutchins Theme 1 – Essentials of General Pathology...

School of Dentistry Faculty of Medicine & Health Illness and Well-being ( DSUR3210) Cell injury and cell death Dr Gordon Hutchins Theme 1 – Essentials of General Pathology Pathology Lecture 2 (PL02) Objectives Be aware of the three broad cellular responses that can occur as a result of cellular stress. List the general broad categories of injurious agents that cause cell injury. Be aware of the basic mechanisms by which cell injury occurs. Describe the morphological features of reversible cell injury and give an example of a clinical situation where reversible cell injury can be seen histologically. Describe the key difference(s) between apoptosis and necrosis. Describe the different morphological patterns of necrosis. Give an example of how necrosis may be exploited for clinical diagnosis. Be aware of the physiological and pathological circumstances where apoptosis can occur. Have insight into the main pathways and general mechanisms of apoptosis. Be aware of the common cellular adaptations that can occur as a result of cellular stress. Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Cellular response to stress and injury Three responses to cellular stress: 1. Adaption 2. Reversible cell injury 3. Irreversible cell injury/death HOMEOSTASIS 3. CELL DEATH INABILITY TO ADAPT 2. CELL INJURY 1. ADAPTION Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Cellular response to stress and injury: The heart as an example… Illness & Well-Being Robbins & Cotran Pathologic Basis of Disease, 10t h Ed, Figure 2.2 School of Dentistry DSUR3210 Faculty of Medicine & Health Causes of cell injury and death Oxygen deprivation / deficiency (AKA hypoxia) Physical / environmental Chemical agents / toxins / drugs Infectious agents Immunologic reactions Genetic derangements Nutritional imbalances Ageing Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury Cellular response to injury depends on the type, duration and severity of the insult. Consequences depend on the type, state and adaptability of the cell. Injurious agent → simultaneously trigger multiple interconnected mechanisms. Cell injury can result if any of the following cellular processes are disrupted: 1. ATP production (via effects on mitochondrial aerobic respiration) 2. Mitochondrial integrity (independent of ATP) 3. Plasma membrane integrity 4. Protein synthesis, folding, degradation and re-folding 5. Genetic (DNA) integrity Illness & Well-Being Robbins & Cotran Pathologic Basis of Disease, 10t h Ed, Figure 2.2 School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury Six broad mechanisms responsible for cell injury: – ALL MECHANISMS ARE GENERALLY INTER-RELATED – Highly complex and difficult to assign a dominant mechanism to specific injury Illness & Well-Being Robbins & Cotran Pathologic Basis of Disease, 8t h Ed, Figure 1.16, page 18 School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury: 1. ATP depletion Adenosine triphosphate (ATP) ATP is critical for energy dependent functions – Membrane transport – Maintenance of ionic gradients (e.g. Na+, K+, and Ca2+) – Protein, DNA & RNA synthesis Efficient production of ATP requires O2 Impaired production / depletion can occur in hypoxia and toxins (e.g. cyanide) Mitochondrial damage also Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury: 1. ATP depletion 5% - 10% reduction in ATP levels → critical cellular damage Failure of Na+ / K+ ATPase pumps – Failure of ionic gradients Hypoxia → anaerobic (inefficient) respiration – Glycolysis → lactic acid → ↓pH (acidosis) Enzyme failure Disruption of protein synthesis / folding Irreversible damage to membranes Formation of reactive oxygen species (ROS) Illness & Well-Being Robbins & Cotran Pathologic Basis of Disease, 8t h Ed, Figure 1.18, page 19 School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury: 2. Mitochondrial damage Many injurious agents can damage mitochondria – Direct e.g. hypoxia, toxins, radiation – Indirect e.g. ↑Ca2+ / oxidative stress / phospholipid breakdown Early damage reversible Sustained damage → – Membrane permeability transition pore (MPTP) – MPTP impairs oxidative phosphorylation → ↓ATP – Reactive oxygen species formation Specific damage → leakage of proteins → apoptosis Illness & Well-Being Robbins & Cotran Pathologic Basis of Disease, 10t h Ed, Figure 2.19 School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury: 3. Increased intra-cellular calcium Cytosolic calcium normally low ATP dependent pumps / selective permeability Hypoxia / toxins → pump failure – ↑Ca2+ → release of Ca2+ from mitochondria / ER – ↑Ca2+ → ↑membrane permeability → ↑Ca2+ ↑Ca2+ activates harmful intracellular enzymes – ATPases / phospholipases / endonucleases – Leads to ↓ATP / cell membrane / DNA damage Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury: 4. ROS/ free radical damage Free radicals = single unpaired electron ROS = type of oxygen-derived free radical → highly reactive Normal by-products of cellular respiration (mitochondria) – Limited amounts, limited life due to reactivity – Mechanisms to counteract → enzymes e.g. SOD / anti-oxidants Increased (pathological) ROS production = “oxidative stress” – Ionising radiation / chemicals – Ischaemia-reperfusion injury – Metals (iron / copper) or chemicals (CCl4) – Nitric oxide – inflammation Cellular effects – Damage cell membrane/ lipids / nucleic acid breaks / protein oxidation & fragmentation Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury: 4. ROS/ free radical damage Illness & Well-Being Robbins & Cotran Pathologic Basis of Disease, 10t h Ed, Figure 2.21 School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury: 5. Membrane damage Early loss of selective membrane permeability common in most forms of cellular injury Esp. oxygen deprivation Damage – Direct – bacterial / viral / immune proteins – Indirect via (↑Ca2+ / ↓ATP / ROS) Increased permeability Lysosomal membrane damage – Intra-cellular release digestive enzymes – Leads to auto-digestion Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury: 6. DNA damage & protein mis-folding Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury: 6. DNA damage & protein mis-folding Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Mechanisms of cell injury Six broad mechanisms responsible for cell injury: – ALL MECHANISMS ARE GENERALLY INTER-RELATED – Highly complex and difficult to assign a dominant mechanism to specific injury Illness & Well-Being Robbins & Cotran Pathologic Basis of Disease, 8t h Ed, Figure 1.16, page 18 School of Dentistry DSUR3210 Faculty of Medicine & Health Reversible cell injury Above mechanisms can be offset if insult is mild / transient. Reversible cell injury Illness & Well-Being Robbins & Cotran Pathologic Basis of Disease, 10t h Ed, Figure 2.1 School of Dentistry DSUR3210 Faculty of Medicine & Health Reversible cell injury: Morphological features Functional / structural alterations occurring in mild and/or early injury that reverse upon removal of the damaging stimulus. Two microscopic features: – Cellular swelling – Fatty change Ultrastructural features: – Plasma membrane blebbing – Mitochondrial swelling – ER dilation – Chromatin clumping Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Reversible cell injury: Morphological features AKI (early) - Kidney Hepatic steatosis Cellular swelling Fatty change (fatty liver) Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Irreversible cell injury / cell death Two main forms of cell death: APOPTOSIS – Tightly controlled ‘programmed cell death’ – Cell contents contained – No release contents / surrounding inflammation NECROSIS – Membrane breakdown – Leakage of cell contents – Into tissues (inflammation) Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Irreversible cell injury / cell death Two main forms of cell death: APOPTOSIS – Tightly controlled ‘programmed cell death’ – Cell contents contained – No release contents / surrounding inflammation NECROSIS – Membrane breakdown – Leakage of cell contents – Into tissues (inflammation) Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Necrosis versus apoptosis FEATURE NECROSIS APOPTOSIS INCREASED REDUCED CELL SIZE (CELL SWOLLEN) (CELL SHRUNKEN) PYKNOSIS (going) NUCLEUS KARYOHEXIS (going) FRAGMENTATION / CONDENSATION KARYOLYSIS (gone) DISRUPTED PLASMA MEMBRANE INTACT (SPILLING OF CONTENTS) NEARBY INFLAMMATION ALMOST ALWAYS NEVER PHYSIOLOGICAL BUT MAY BE PHYSIOLOGICAL / PATHOLOGICAL PATHOLOGICAL PATHOLOGICAL Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Morphological patterns of necrosis COAGULATIVE – Tissue with connective tissue → shape / structure preserved COLLIQUATIVE – Minimal connective tissue → ‘liquefies’ CASEOUS – ‘Cheese’-like necrotic debris in defined border GANGRENE – DRY –coagulative necrosis e.g. distal limb / WET – with infection FAT – Focal necrosis in fat due to action of lipases (also trauma) FIBRINOID – Occurs with damage to vessel walls → pink material (fibrin-like i.e. fibrinoid) Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Guess the necrosis! Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Apoptosis “Cellular suicide” / programmed cell death Tightly regulated Removes unwanted cells without damaging surrounding tissues Can be physiological or pathological Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Apoptosis: Physiological examples Embryogenesis – Removal of unwanted / excessive cells during development Involution of hormone-dependent tissues – Apoptosis on hormone withdrawal – E.g. endometrial breakdown during menstruation, regression of breast post-lactation Control cell turnover in proliferating cell populations – e.g. in colon to maintain a constant cell number (homeostasis). Elimination of potentially harmful self-reactive lymphocytes Death of host cells after immune response Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Apoptosis: Pathological DNA damage – Radiation / drugs, direct or indirect via free radicals – Important as prevents propagation of cells with DNA damage Accumulation of misfolded proteins Infections – Directly e.g. HIV – Indirectly e.g. host immune response Pathological atrophy – In some situations Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Apoptosis: 2 main pathways Mitochondrial (intrinsic) pathway – Loss of survival signals, DNA damage etc. – Leakage of pro-apoptotic proteins (mitochondria) – Activates caspases Death receptor (extrinsic) pathway – Binding of ligand to a cell surface receptor – Activates caspases Caspase activation is common to both – Fragmentation of DNA / nuclei – Formation of “Apoptotic body” → cell fragments for phagocyte absorption Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Morphology of apoptosis Cell shrinkage Chromatin condensation Cytoplasmic blebs Apopototic bodies (AB) Phagocytosis of Abs No surrounding damage Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Necrosis versus apoptosis: A summary Illness & Well-Being Robbins & Cotran Pathologic Basis of Disease, 10t h Ed, Figure 2.4 School of Dentistry DSUR3210 Faculty of Medicine & Health Necrosis versus apoptosis: A summary Necrosis Apoptosis Illness & Well-Being Robbins & Cotran Pathologic Basis of Disease, 10t h Ed, Figure 2.4 School of Dentistry DSUR3210 Faculty of Medicine & Health Cell death and clinical diagnosis Myocardial infarction – Necrosis → myocardial enzymes released into blood – Troponin I / T, CK-MB, LDH, AST Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Cell death and clinical diagnosis Myocardial infarction – Necrosis → myocardial enzymes released into blood – Troponin I / T, CK-MB, LDH, AST Pancreatitis – Necrosis →enzymes released into blood – Amylase ↑↑↑↑ – Lipases → Fat necrosis → saponification → ↓[Ca2+] Apoptosis – Seen microscopically e.g. liver disease, GVHD Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Cellular Adaption Reversible changes in the size, number, phenotype, metabolic activity, or functions of cells in response to changes in their environment Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Cellular Adaption Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Hypertrophy An increase in the size of cells resulting in an increase of organ size – No new cells, just larger – synthesis of more structural components of the cells Physiological – Body-building - ↑ muscle fibre size ↑ load stress (weight-lifting) Pathological – Cardiac hypertrophy - ↑ myocyte size circulatory stress hypertension Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Hyperplasia An increase in the number of cells in an organ or tissue usually resulting in increased mass of the organ or tissue – Usually in response to hormones / growth factors in tissues with dividing cells Physiological – Hormonal – e.g. Breast in pregnancy Pathological – e.g. – benign prostatic hyperplasia NOT neoplasia – But neoplastic change can occur in hyperplastic tissues – Endometrial hyperplasia Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Atrophy Reduced size of an organ or tissue resulting from a decrease in cell size and number Physiological – Embryology, post-partum uterus Pathological – Decreased workload – Denervation – Diminished blood supply – Inadequate nutrition – Loss of endocrine stimulation – Pressure Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Metaplasia Change in which one differentiated cell type is replaced by another cell type Adaptive substitution of cells that are sensitive to stress by cell types better able to withstand adverse environment (usually inflammatory) Oesophagus – Acid reflux → squamous cells → gastric-like columnar epithelium (Barrett’s) Lungs – Cigarette smoke → respiratory-type columnar cells → squamous cells Cervix – Vaginal ↓pH → columnar cells (endocervix) → squamous cells (ectocervix) Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Metaplasia Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Objectives Be aware of the three broad cellular responses that can occur as a result of cellular stress. List the general broad categories of injurious agents that cause cell injury. Be aware of the basic mechanisms by which cell injury occurs. Describe the morphological features of reversible cell injury and give an example of a clinical situation where reversible cell injury can be seen histologically. Describe the key difference(s) between apoptosis and necrosis. Describe the different morphological patterns of necrosis. Give an example of how necrosis may be exploited for clinical diagnosis. Be aware of the physiological and pathological circumstances where apoptosis can occur. Have insight into the main pathways and general mechanisms of apoptosis. Be aware of the common cellular adaptations that can occur as a result of cellular stress. Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health Illness & Well-Being School of Dentistry DSUR3210 Faculty of Medicine & Health