Lecture 1 - Cell Injury and Death 2023 PDF

Cellular Injury & Death The Basis of All Pathology Andrew J Gow [email protected] Physiology vs Pathology • Physiology is the study of the physical (often termed natural philosophy) • Pathology is the study of suffering (often considered the disease discipline) • Pathophysiology is the study of the...

Cellular Injury & Death The Basis of All Pathology Andrew J Gow [email protected] Physiology vs Pathology • Physiology is the study of the physical (often termed natural philosophy) • Pathology is the study of suffering (often considered the disease discipline) • Pathophysiology is the study of the nature of suffering Growth in Pathology and Physiology Concentric and Eccentric Hypertrophy Complex Function in Pathology and Physiology Pathology • Etiology – Origin of disease (Why) • Pathogenesis – Development of disease (How) Injury and Death are a Continuum Apoptosis vs Necrosis Necrosis Apoptosis Cell size Enlarged (swelling) Nucleus Pyknosis → karyorrhexis → karyolysis Reduced (shrinkage) Fragmentation into nucleosome-sized fragments Plasma membrane Disrupted Cellular contents Enzymatic digestion; may Intact; may be released in leak out of cell apoptotic bodies Adjacent inflammation Frequent Absent Physiologic or pathologic role Invariably pathologic (culmination of irreversible cell injury) Often physiologic; means of eliminating unnecessary cells; may be pathologic Intact; altered structure, especially orientation of lipids Injury and Death are a Continuum Etiology of Cellular Death • • • • • Causative agent Target within the cell Intrinsic vs Extrinsic factors Accumulation of error Imbalance Causative Agent Affects Death Pathway Cellular Injury and Necrosis • Cycle of injury and response • Energy requiring • Stimulus exceeds response leads to death • Programmed vs Unprogrammed • Protein Synthesis??? Nuclear Changes in Necrosis • Chromatin condensation • Nuclear fragmentation • Nucelar dissolution Apoptosis Condition Physiologic Mechanism of Apoptosis During embryogenesis Loss of growth factor signaling (presumed mechanism) Turnover of proliferative tissues (e.g., intestinal epithelium, lymphocytes in lymph nodes and thymus) Loss of growth factor signaling or survival signals (presumed mechanism) Involution of hormone-dependent tissues (e.g., endometrium) Decreased hormone levels lead to reduced survival signals Decline of leukocyte numbers at the end of immune and inflammatory responses Loss of survival signals as stimulus for leukocyte activation is eliminated Strong recognition of self antigens Elimination of potentially harmful self- induces apoptosis by both the reactive lymphocytes mitochondrial and death receptor pathways Pathologic DNA damage Activation of proapoptotic BH3-only proteins Accumulation of misfolded proteins Activation of proapoptotic BH3-only proteins, possibly direct activation of caspases Infections, especially certain viral infections Activation of proapoptotic proteins or caspases by viral proteins; killing of infected cells by cytotoxic T lymphocytes (CTLs), which activate caspases Apoptosis • Intrinsic and Extrinsic pathways • Calcium and Cytochrome c • BCL genes • Phosphorylation required • Protein synthesis required Autophagy • Cellular response to nutrient stress • Cellular recycling • Energetic process • Requires protein synthesis Initiating Events • Loss of membrane integrity • Oxidative stress STRES –Energetic imbalance • Hypoxia • Ischemia • Cellular overload –Accumulation • Ageing and failure to maintain Membrane Integrity ER Stress Response • Mistakes happen – Leads to misfolded proteins • ER source of protein synthesis – Senses Misfolds • Low level – UPR • Excess leads BH-3 activation – Caspase activation – Apoptosis • CFTR, Hypercholesteremia (LDL-R) Proteasome Function and Unfolded Proteins • • • • Proteasome proteolyses ubiquitinated substrates It is an endopeptidase complex that can be compared to a ‘trash can’ Undegradable protein aggregates play a role in a number of neurodegenerative diseases – – Polyglutamine repeats Parkin Uncleavable aggregates lead to cellular dysfunction and death Oxidative Stress • • • • Production of Reactive Oxygen Species (ROS) – Fact of Life Oxidative modifications is key (Free radicals????) Reperfusion injury Superoxide, Hydrogen peroxide, Hydroxy radical, Peroxynitrite – Nitric Oxide Synthase, NADPH Oxidase, Mitochondrial Respiration Hypoxia & Ischemia • Hypoxia – Low oxygen level – Reduces metabolic capacity • Ischemia – Loss of flow – Low oxygen, low supplies, low waste removal • Excess Injury Accumulation of Material Cellular Ageing Stem vs Somatic Cells Summary of Mechanisms of Cell Injury • • • • • • 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 and is 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., by radiation, can also induce apoptosis if it is not repaired. Hypoxia and ischemia lead to ATP depletion and failure of many energydependent functions, resulting first 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. Response to Cell Death Metaplasia • Growth of other • Death of somatic cells leads to replacement • Different from Dysplasia – Mature vs immature Hyperplasia Inflammatory Lipid Signaling Inflammation as Repair Ischemia & Excitotoxicity: Keys to Neuronal Loss