1. FM2004 PM2004 Cell Injury & Death 23-24.pdf

FM2004 & PM2004 Cell Injury and Death Dr Collette Hand UCC Department of Pathology [email protected] January 2024 Dr C. Hand Canvas Information Screen shots from Canvas Dr C. Hand Weekly content Module Access by link on home page or under Modules Canvas Content Topic Module Dr C. Hand Module Timetables...

FM2004 & PM2004 Cell Injury and Death Dr Collette Hand UCC Department of Pathology [email protected] January 2024 Dr C. Hand Canvas Information Screen shots from Canvas Dr C. Hand Weekly content Module Access by link on home page or under Modules Canvas Content Topic Module Dr C. Hand Module Timetables Available – Canvas – Online Timetable (UCC) any school/ prog / dept timetables are separate Lectures: all programmes together Practical and Clinicopathological cases (CPC) Sessions what does CPC mean? – Weeks 27-33, 36-37 (wks 34, 35 Easter recess) – FM2004: Med2: divided into Groups A&B, C&D, Monday pm and Friday am – FM2004: Dent2: Tuesday pm – PM2004: Wednesday pm 4 topics 1. Cellular Pathology 3. Medical Microbiology and Infectious Disease (MMID) Subject to change 2. Genetics 4. Immunology -> Canvas notification TBC: not released until end of course Dr C. Hand Module Assessment Details on Canvas CA1 CA2 Summer TOTAL 25 marks 25 marks 150 marks 200 Marks EMQ/MCQ 04-Mar-24 EMQ/MCQ 15-Apr-24 EMQ/MCQ Apr/May-24 first two topics second two topics very close to other exams FM2004: Pass = ≥ 100/200 marks (50%) – Oral Examination in Summer ** check Date PM2004: Pass = ≥ 80/200 marks (40%) – No Oral examination General – You do not need to pass each assessment independently. – ie if you fail a CA exam you are not required to repeat it once you pass the module overall at Summer Dr C. Hand Textbooks R9 R10 Robbins & Cotran Pathologic Basis of Disease U6 U7 Underwood General & Systemic Pathology RBP9 RBP10 Kumar, Abbas, Aster Robbins Basic Pathology Robbins & Cotran Atlas of Pathology A2 W5 Young, Stewart, O’Dowd Wheater’s Basic Pathology Dr C. Hand A word about information 1 Dr C. Hand A word about information 2 Dr C. Hand Introduction to Pathology The study (logos) of suffering (pathos) Investigation of the causes of disease and the associated changes a level of cells, tissues and organs – -> signs and symptoms of patient Aetiology: cause of disease Pathogenesis: mechanism causing the disease enlarged spleen abnormal skin cells Morphology: gross or microscopic appearance of cells / tissues – Evolution: Gross - microscopic - cellular – biochemical / molecular changes Diagnosis, complications, prognosis, management Pathology provides the scientific foundation for the practice of medicine Dr C. Hand Cell responses to stress / injury RBP9: Fig 1.1 RPB10: Fig 2.2 R9/R10: Fig 2.1 Dr C. Hand Cell Injury causes Q Suggestions? Dr C. Hand Cell Injury causes A Oxygen deprivation: hypoxia, ischaemia Physical: trauma, temp, radiation Toxins Infectious agents Immune reactions Genetic abnormalities Nutritional imbalances Aging Dr C. Hand Factors affecting cell damage Duration of injury how long was the cell without oxygen Nature of injurious agent how bad is the cut Proportion and type of cells damaged Ability of tissue to regenerate – any thoughts? Dr C. Hand Regeneration Adult cells: 3 groups -> ability to proliferate Labile – Continuously dividing/ proliferating – eg surface epithelia, lining mucosa, BM & haematopoietic cells Stable (quiescent) – Able to undergo rapid division in response to stimuli – eg liver, kidney, pancreas, fibroblasts, vascular smooth muscle Permanent – Non-dividing cells; – no mitosis postnatally – eg CNS, nerve cells Dr C. Hand Adaptive Responses Hyperplasia Hypertrophy Atrophy Metaplasia (Dysplasia) RBP9: Fig 1.1 RPB10: Fig 2.2 R9/R10: Fig 2.1 Dr C. Hand Hyperplasia & Hypertrophy Enlargement of an organ or tissue plasia = growth cell number is increased. cell size is increased. U6/U7: Fig 4.12 What types of cells? Dr C. Hand Hyperplasia Enlargement of an organ or tissue due to an increase in the NUMBER of the cells Increase functional capacity of tissue when required HORMONAL eg breast in puberty Increase tissue mass after damage or loss COMPENSATORY eg liver damage Causes – growth factors, receptors Physiologic or pathologic – wound healing, neoplasia (uncontrolled**) Dr C. Hand Hypertrophy Enlargement of an organ or tissue due to an increase in the SIZE of the cells No new cells, just larger – synthesis of components, not cell swelling Muscle hypertrophy in athletes – Skeletal muscles, left ventricle of heart Physiologic or pathologic Dividing cells: hyperplasia + hypertrophy Non dividing cells: hypertrophy only Dr C. Hand Physiologic hypertrophy R9: Fig 2.3; R10: Fig 2.25; RBP9: Fig 1.3; RBP10: Fig 2.20; Physiological hypertrophy of the uterus during pregnancy A, Gross appearance of a normal uterus (right) and a pregnant uterus (left). B, Small spindle-shaped uterine smooth muscle cells from a normal uterus (left) C, large plump cells in pregnant uterus (right). Dr C. Hand Atrophy Pathological or physical cellular or organ shrinkage Shrinkage of the size of the cell by loss of cell substance Reduced supply of nutrients and growth factors Decrease in the size of a cell or tissue Physiologic or pathologic – eg: skeletal muscle atrophy after bed rest, loss of hormone stimulation, denervation Dr C. Hand Atrophy figure R9: Fig 2.5; R10: Fig 2.27; RBP9 Fig 1.4; RBP10 Fig 2.22 Atrophy A, Normal brain of a young adult. B, Atrophy of the brain in an 82-year-old male with atherosclerotic cerebrovascular disease, resulting in reduced blood supply. Loss of brain substance narrows the gyri and widens the sulci. The meninges have been stripped from the right half of each specimen to reveal the surface of the brain Dr C. Hand Metaplasia Reversible change in the character of a tissue from one mature cell type to another Reversible change in which one adult cell type is replaced by another adult cell type Smoking – normal columnar epithelium replaced by stratified squamous – squamous more rugged – loss of specific function: mucous secretion Influences that predispose to metaplasia, if persistent, may induce malignant transformation in metaplastic epithelium Dr C. Hand Metaplasia Figure Metaplasia of columnar to squamous epithelium A, Schematic diagram B, Metaplasia of columnar (left) to squamous epithelium (right) in a bronchus R9: Fig 2.6; R10: Fig 2.28; RBP9: Fig 1.5, RBP10 Fig 2.23 Dr C. Hand Dysplasia Abnormal growth and differentiation of a tissue – – – – – – Disordered growth Loss of uniformity of individual cells Loss of architectural orientation Pleomorphism can alter their morphology Increase in mitotic figures cells in the process of dividing Hyperchromatic nuclei that are abnormally large Reversible in early stages Often pre- neoplastic, but does not necessarily progress to cancer Dr C. Hand Cervix W5: Fig 7-1 Dr C. Hand Dysplasia- cervix Normal cervix stratified squamous epithelium - proliferation restricted to basal (B) layer - Cells are small, uniform, darkly stained. - cells mature towards surface; more pink - Near surface, cells become more flattened, N:C ratio decreases W5: Fig 7-1 Dysplastic cervical epithelium- disruption of orderly maturation sequence. - Cells exhibit larger than normal nuclei. - Mitotic figures (M) seen above basal layer. - Cells are pleomorphic - N:C ratio greater than usual. -Surface cells with large nuclei. Dr C. Hand Skin W5: Fig 7-1 Dr C. Hand Dysplasia- skin Normal skin Normal stratification W5: Fig 7-1 Dysplastic skin - Multinucleate cells (N) extending up strata - Mitotic figures (M) seen above basal layer Dr C. Hand - thick layer of keratin : clinically evident, scaling Cell Injury Cell is unable to adapt ? ? Is the injury reversible or irreversible? – depends on the injury and the cell RBP9: Fig 1.1 RPB10: Fig 2.2 R9/R10: Fig 2.1 Dr C. Hand Reversible Cell Injury 2 morphologic correlates 1. Cell swelling failure of energy dependent pumps in plasma membrane -> loss of ionic and fluid homeostasis 2. Fatty changes hypoxic, toxic injury -> lipid vacuoles in the cytoplasm Dr C. Hand Intracellular deposits & calcifications Abnormal deposits of materials in cells / tissues – Excessive intake/production or defective transport / catabolism Lipids – Fatty change, cholesterol deposition Pigments – Typically indigestible eg carbon, iron Cytoplasm, organelles (eg lysosome), nucleus Pathologic calcification – Dystrophic calcification: sites of cell injury and necrosis – Metastatic calcification: deposition of Ca in normal tissue, hypercalcaemia eg parathyroid hormone excess Dr C. Hand Cell injury 1. Cellular response to injury depends on type of injury, duration and severity 2. Consequences of cell injury depend on type state and adaptability of injured cell 3. Cell injury results from functional and biochemical abnormalities in one or more of several essential cellular components any thoughts? Dr C. Hand Mechanisms of Cell Injury R9: Fig 2.16; RBP9: Fig 1.14; RBP10: Fig 2.15 Complex- usually multiple mechanisms Dr C. Hand Cell Death RBP9: Fig 1.1 RPB10: Fig 2.2 R9/R10: Fig 2.1 Dr C. Hand Necrosis only when things arn't normal Pathological process Cell death due to irreversible cell injury Progressive degradative action of enzymes – enzymes from cell (autolysis) or inflammatory cells [cells placed in fixative are dead but not necrotic] Loss of membrane integrity- leakage Inflammatory reaction Neighbouring cells affected Dr C. Hand Necrosis - morphology Cells are pink, larger Nuclear changes assume one of 3 patterns, all due to breakdown of DNA and chromatin – Pyknosis- nucleus is shrunken and dark – Karyolysis- nuclear dissolution – Karyorrhexis- nuclear fragmentation Dr C. Hand Types of Necrosis Mass of necrotic cells –> several morphological patterns Depends on tissue and causative agent – Coagulative – Liquefactive – Caseous – Gangrene – Fat necrosis Dr C. Hand Coagulative, Liquefactive Necrosis Coagulative Most common type of necrosis Preservation of general tissue architecture (days) Characteristic of hypoxic death of cells in all tissues except the brain Liquefactive Bacterial / fungal infections Hypoxic death in CNS Liquefaction digests the dead cells Tissue become liquid viscous mass Dr C. Hand Coagulative, liquefactive necrosis outline of what it was debris R7: Fig 1.19 A, Kidney infarct exhibiting coagulative necrosis, with loss of nuclei and clumping of cytoplasm but with preservation of basic outlines of glomerular and tubular architecture. B, A focus of liquefactive necrosis in the kidney caused by fungal infection. The focus is filled with white cells and cellular debris, creating a renal abscess that obliterates the normal architecture. Dr C. Hand Caseous, Liquefactive Necrosis Liquefactive necrosis. An infarct in the brain, showing dissolution of the tissue - Tissue -> liquid - Bacterial / fungal infections - Hypoxia in CNS R9: Fig 2.12; R10 Fig 2.8; RBP9: Fig 1.10; RBP10: Fig 2.7 Caseous Necrosis. sounds like TB Tuberculosis of the lung, with a large area of caseous necrosis containing yellow-white and cheesy debris -TB infection -Caseous (cheeselike) : friable white appearance R9: Fig 2.13; R10 Fig 2.9; C. Hand RBP9: Fig 1.11; RBP10:DrFig 2.8 Gangrene Not a specific pattern cell death Term often applied to limb / intestine – lost blood supply -> necrosis (gen. coagulative) Necrosis with putrefaction of tissue Dry gangrene – coagulative necrosis Wet gangrene – coagulative necrosis + infection -> liquefactive action of bacteria + inflammatory cells Dr C. Hand Fat Necrosis Focal areas of fat destruction Seen in acute pancreatitis – released pancreatic enzymes -> necrosis of adipose tissue – released fatty acids + calcium -> visible chalky white areas (fat saponification) R9: Fig 2.14; R10 Fig 2.9; RBP10: Fig 2.9 A2: Fig 9.8 Fat necrosis consists of steatocytes that have lost their nuclei and whose cytoplasm has a granular pink C. Hand appearance, pronounced here in theDrright Apoptosis quiet and controlled Physiological or pathologicalE.G.process Cancer E.G. In development "make things look right" Energy dependent Regulated intracellular program – enzymes degrade cells own nuclear DNA and cytoplasmic proteins Membrane intact No inflammatory reaction* Individual cells affected Dr C. Hand Apoptosis - morphology costs us energy to control it Cell shrinkage cytoplasm is dense normal sized organelles are tightly packed Chromatin condensation Nucleus may break – 2 or more fragments Formation of - cytoplasmic blebs - apoptotic bodies Phagocytosis by neighbouring cells Rapidly degraded within lysosomes Adjacent healthy cells migrate/ proliferate to fill space Dr C. Hand Apoptosis figures Early Stage Later Stage U6: Fig 4.6 Apoptosis Section of skin in case of GVHD- individual cell death as a result of immune injury Dr C. Hand Apoptosis v. Necrosis U6/U7 Table 4.1 Feature Apoptosis Induction May be induced by physiological Invariably due to pathological or pathological stimuli injury Extent Biochemical events Necrosis Single cells Energy-dependent fragmentation of DNA by endogenous endonucleases Cell groups Energy failure Impairment or cessation of ion homeostasis Lysosomes intact Lysosomes leak lytic enzymes Cell membrane Maintained Lost integrity Cell shrinkage and fragmentation Morphology to form apoptotic bodies with Cell swelling and lysis dense chromatin Inflammatory None Usual response Ingested (phagocytosed) by Fate of dead Ingested (phagocytosed) by neutrophil polymorphs and cells neighbouring cells macrophages Defence, and preparation for Outcome Cell elimination doesn't cost us energy Dr C. Hand repair costs energy Ultrastructural changes R9: Fig 2.5 RBP9: Fig 1.6 RBP10: Fig 2.3, Fig 2.11 Dr C. Hand Cell Death: summary Not all bad! Normal in development embryology Homoeostasis Aim of cancer therapy Dr C. Hand Injury to cardiac cells cant make new ones RBP9: Fig 1.2; RBP10: Fig 2.21; R9: Fig 2.2 The relationships between normal, adapted, reversibly injured, and dead myocardial cells Dr C. Hand Cell Injury and Death RBP9: Fig 1.1 RPB10: Fig 2.2 R9/R10: Fig 2.1 Dr C. Hand Review Adaptive Responses – Hyperplasia – Atrophy – (Dysplasia) - Hypertrophy - Metaplasia Apoptosis – Characteristics Necrosis – Characteristics, types Dr C. Hand Learning Outcomes On successful completion of this class, students should be able to: Identify the cells and molecules involved in pathological processes. Outline cellular responses and adaptations to injury. Define and recognise types of cellular adaptation. Compare and contrast cell death by necrosis and apoptosis. Distinguish different types of necrosis. Dr C. Hand