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01. cell injury-2018_11_19 -student copy.pptx
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- 2. The scientific foundationfor the practice of medicine Pathology???
- 3. Pathology (pathos “disease”+ logos “reason”) is the study of the links between diseases and the basic science
- 4. Aetiology “The origin ofthe disease” Pathogenesis “Steps in the development of disease” The scientific foundation for the practice of medicine
- 6. Aspects of adisease process • Cause (etiology) • Biochemical and molecular mechanisms of its development (pathogenesis) • Structural alterations induced in the cells and organs of the body (morphologic changes) • Functional consequences of these changes (clinical manifestations). (These four steps are the core of pathology)
- 7. General pathology Systemic pathology Respiratory Cardiovascular Renal GIT Male and femalegenital tract Breast CNS Haematolymphoid endocrine
- 8. Pathologist is aperson identifying diseases based on the examination of cells , tissues, fluids removed from the body.
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- 14. Learning outcomes • Definecell injury, reversible cell injury and irreversible cell injury. • List the causative agents / injurious stimuli. • Briefly outline the mechanisms of cell injury. • Describe the different morphological patterns / appearances of cell injury and list the clinical situations in which they occur Reversible cell injury Irreversible cell injury - Necrosis and its patterns, - Apoptosis,
- 15. Homeostasis The normal cell….. •confined to a fairly narrow range of function and structure by its state of metabolism, differentiation, & specialization; • by constraints of neighboring cells; and by the availability of metabolic substrates. • But able to handle physiologic demands, maintaining a steady state called homeostasis.
- 17. Cellular adaptations tostress • Adaptation- Reversible changes in the number, size, phenotype, metabolic activity or functions of cells in response to changes in the environment. Adaptation Physiological causes Pathological causes
- 18. Adaptive responses 1) Increasein the size of cells and its functional activity (hypertrophy) 2) Increase in their number (hyperplasia) 3) Decrease in the size and metabolic activity of cells (atrophy) 4) Change in the phenotype of cells (metaplasia) When the stress is eliminated the cell can recover to its original state without any harmful consequences.
- 19. Cell injury When thecells are stressed to a limit exceeding the adaptive responses or When cells are exposed to inherently damaging agents or suffer from intrinsic abnormalities (DNA, proteins) the sequence of events that follows is termed cell injury.
- 20. Cell injury cont…. •Reversible up to a certain point. • If the stimulus persists or is severe enough from the beginning, result irreversible injury and ultimately undergoes cell death.
- 21. The relationship betweennormal, adapted, reversibly injured, and dead myocardial cells.
- 23. Causes of cellinjury • Oxygen deprivation • Physical agents • Chemical agents and drugs • Infectious agents • Immunological reactions • genetic derangements • Nutritional imbalances • Aging
- 24. • Reduced oxyen oxygendeficiency in blood ischemia (blood flow deficiency) loss of O2 carrying capacity (CO, anaemia) poisoning • Chemical agents: drugs ( Eg-Paracetamol - P450 catalyzed oxidation to toxic metabolite) alcohol, narcotics • Physical agents: trauma, heat, radiation, electric shock • Infections- Viruses, bacteria, fungi, protozoa
- 25. • Immunological reactions:including anaphylaxis and loss of immune tolerance that results in autoimmune disease • Genetic defects: sickle cell disease, inborn errors of metabolism • Nutritional defects: malnutrition, vitamin deficiencies, obesity leading to type II DM, defective fat metabolism leading to atherosclerosis • Aging: degeneration as a result of repeated trauma, and intrinsic cellular senescence
- 26. Cell injury…… These aetiologicalfactors cause cell injury by different mechanisms. Cell response to injury is not an all-or-nothing phenomenon. ❖Response to a given stimulus depends on type, duration and severity of injury and type, state, genetic make up and adaptability of cell.
- 27. Multiple biochemical alterationsmay be triggered by any injurious insult. • The first effect of all injuries is on the biochemical and molecular level. • Functional derangement happens next. • Ultrastructural changes seen by electron microscopy follow. • Then light microscopic changes occur. • The last visible change is at the gross; macroscopic level.
- 28. Sequential development ofbiochemical & morphologic changes in cell injury.
- 29. Biochemical mechanisms responsiblefor reversible cell injury • Mitochondrial damage • Influx of intracellular calcium • Increased permeability of cell membranes • Accumulation of damaged DNA and misfolded proteins
- 30. 1) Mitochondrial damage Mitochondrialdamage ATP depletion failure of energy-dependent cellular functions necrosis; under some conditions, leakage of proteins activate apoptosis Membrane transport, protein synthesis, lipogenesis, Phospholipid turnover Form reactive O2 species Form high conductance channel in mitochondrial membrane
- 31. Functional and morphologic consequencesof decreased intracellular ATP during cell injury
- 32. • Damage tomitochondria cause high conductance channel formation in the mitochondrial membrane. (mitochondrial permeability transition pore). • Leads to loss of mitochondrial membrane potential and pH changes. • This further compromise oxidative phosphorylation.
- 33. Free radicles • Freeradicals are chemical species with a single unpaired electron in an outer orbit. • Free radicals are chemically unstable and therefore readily react with other molecules, resulting in chemical damage.
- 34. Intracellular Sources ofFree Radicals • Normal redox reactions generate free radicals • Ionizing radiation (UV, X-rays) can hydrolyze water into hydroxyl (OH •) and hydrogen (H •) free radicals • Metabolism of exogenous chemicals (Eg CCl4) can generate free radicals • Nitric oxide (NO) can act as a free radical Free radical generation is a “physiological” antimicrobial reaction.
- 35. Neutralization of FreeRadicals • Spontaneous decay • Superoxide dismutase (SOD): 2O 2 • + 2H → O 2 + H 2 O 2 • Glutathione (GSH): 2OH • + 2GSH → 2H 2O + GSSG • Catalase: 2H 2 O 2 → O 2 + H 2 O • Endogenous and exogenous antioxidants (Vitamins E, A, C and β-carotene)
- 36. Free radical inducedinjury If not adequately neutralized, free radicals can damage cells by three basic mechanisms: 1. Lipid peroxidation of membranes: double bonds in polyunsaturated membrane lipids are vulnerable to be attacked by oxygen free radicals. Lipid-radical interaction yield peroxides. 2. DNA fragmentation: Free radicals react with thymine in nuclear and mitochondrial DNA to produce single strand breaks. 3. Protein cross-linking: Free radicals promote sulfhydryl-mediated protein cross-linking, resulting in increased degradation or loss of activity.
- 37. Role of ROSin cell injury
- 38. 2) Influx ofcalcium • Cytosolic free calcium is maintained(Very low concentration) by ATP dependent calcium transporters. • Ischemia and some toxins cause increased cytosolic ca+. • Increased cytosolic ca+ activate enzymes that damage cellular components. (phospholipase, endonuclease,ATPase, Protease) • May also trigger apoptosis.
- 39. T Role ofcytosolic calcium in cell injury
- 40. 3) Increased permeabilityof cellular membranes: • Ischemia, bacterial toxins, viral proteins, a variety of physical and chemical agents lead to membrane damage. • Early loss of selective membrane permeability, ultimately result overt membrane damage. • This is a consistent feature of most forms of cell injury. • May affect – plasma membrane (loss of osmotic balance, loss of cellular contents) – lysosomal membranes (leakage of enzymes into cytoplasm) – mitochondrial membranes.(discussed) • Typically culminate in necrosis
- 41. Decreased PL synthesis IncreasedPL breakdown • ROS • Increased cytosolic ca+ activate proteases which damage cytoskeleton • Lipid breakdown products causing changes in membrane permeability. Mechanism of membrane damage
- 42. • Cells havemechanisms that repair damage to DNA. • But if DNA damage is too severe to be corrected (e.g., after exposure to DNA damaging drugs, radiation, or oxidative stress), the cell initiates a suicide program that results in death by apoptosis. 4) Damage to DNA and Proteins
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- 44. Clinico-pathologic correlations- Eg- • Ischemicand hypoxic injury • Ischemia - reperfusion injury • Chemical injury ( Refer Robbins basic pathology)
- 45. Hypoxic injury • Hypoxiais a condition in which the body or a region of the body is deprived of adequate O2 supply. • The most common cause of cell injury. • Hypoxia leads to cell injury mainly by reducing aerobic respiration.
- 46. • Cells needO2 to generate energy and perform metabolic functions. • Deficiency in 02 result in failure to carry out these activities. • Cell related and injury related factors decide the degree of injury
- 47. Ischemia-reperfusion injury If cellsare reversibly injured due to ischemia, restoration of blood flow can recover the cells. But some instances paradoxically this accelerates injury leading to irreversible injury. Eg: In myocardial and cerebral infarctions after thrombolytic therapy.
- 48. Mechanisms of celldamage in Ischaemic reperfusion injury. • Increased generation of reactive oxygen species. • Subsequent inflammatory reaction. • Calcium overload
- 49. Chemical injury • Directcytotoxic effect • By converting to reactive toxic metabolites. Eg: Cyanide - poisons mitochondrial cytochrome oxidase CCl4 - conversions to free radical CCl3· causing lipid peroxidation
- 50. Cell injury :Morphology Twopatterns of reversible cell injury can be recognized under the light microscope: • Cellular swelling • Cellular fatty change
- 51. Failure of ATP dependention pumps in plasma membranes Inability to maintain ion and fluid homeostasis Cellular swelling Cellular swelling appears whenever cells are incapable of maintaining ionic and fluid homeostasis. • The first manifestation of cell injury. • Resulted by the functional loss of plasma membrane energy- dependent ion pumps. • Reversible. • This pattern is called hydropic change or vacuolar degeneration as well.
- 52. • Macroscopy: enlarged,Increased weight • Microscopy:Small clear vacuoles seen within cytoplasm (represent distended, pinched-off segments of ER). • Swollen organelles within the cell. • Increased eosinophilic staining, which is more pronounced with progression to necrosis (described later).
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- 54. Fatty change occurs inhypoxic injury and various forms of toxic or metabolic injury. • It is manifested by the appearance of small or large lipid vacuoles in the cytoplasm. • Abnormal intracellular accumulation of triglycerides. Eg: hepatocytes, myocardial cell.
- 55. • Macroscopy Fatty liver– enlarged, greasy, yellow cut surface
- 56. • Microscopy: Fattychange
- 57. Reversible injury- intracellular changes(Electronmicroscopic) Plasma membrane Blebbing Blunting Distortion of microvilli Loosening of intercellular attachments nucleus Clumped chromatin ER Dilated ER Detachment of ribosomes Dissociation of polysomes mitochondrial Swelling appearance of amorphous densities (Myelin figures)
- 58. These changes arereversible
- 60. Cell injury –Part11 Irreversible cell injury 2018.11.21
- 61. Learning outcomes • Definecell injury, reversible cell injury and irreversible cell injury. • List the causative agents / injurious stimuli. • Briefly outline the mechanisms of cell injury. • Describe the different morphological patterns / appearances of cell injury and list the clinical situations in which they occur Reversible cell injury Irreversible cell injury - Necrosis & patterns, - Apoptosis
- 63. Irreversible cell injurypatterns Necrosis Apoptosis
- 64. Necrosis • A spectrumof morphological changes that follow cell death in living tissues. • Necrotic cells are unable to maintain membrane integrity and their contents leak out. • Leaked out cellular contents lead to inflammation in the surrounding tissue trying to remove the dead cells. • Lysosomal enzymes of the dying cells and the lysosomal enzymes of leucocytes recruited as part of the inflammatory reaction to dead cells are responsible for digestion of cells.
- 65. Necrosis….. The morphologic appearanceof necrosis is the result of denaturation of intracellular proteins and enzymatic digestion of the lethally injured cell.
- 66. Necrosis-microscopy • Increased eosinophiliaof cytoplasm (loss of cytoplasmic RNA which binds hematoxylin and in part to denatured cytoplasmic proteins which bind the eosin). • A glassy homogeneous appearance (as a result of the loss of glycogen particles). • Cytoplasm becomes vacuolated and appears moth eaten (enzymes have digested the cytoplasmic organelles) • Breakdown of plasma membrane and organelle membranes
- 67. • Abundant myelinfigures. (Dead cells may be replaced by large, whorled phospholipid masses called myelin figures that are derived from damaged cell membranes)
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- 69. Electron microscopic changesof reversible cell injury 1. Plasma membrane and organelle membranes become discontinues 2. Mitochondrial changes, marked swelling and the appearance of large amorphous densities 3. Intracytoplasmic myelin figures 4. Disrupted lysosomes 5. Nuclear changes – dissolved nuclei
- 70. Fate of necroticcell • May persist for sometime or may be digested by enzymes and disappear. • May be replaced by myelin figures which are phagocytosed or further degraded to fatty acids. • Fatty acids can bind calcium and become calcified.
- 71. Patterns of tissuenecrosis: Necrosis of tissues has several morphologically distinct patterns. These are important to recognize because they may provide clues about the underlying cause. • Coagulative • Liquefactive • Caseous • Fat necrosis • Fibrinoid
- 72. Coagulative necrosis • Themost common cause is hypoxia. • All parenchymal tissues undergo coagulative necrosis. ( except brain and abscesses) • Injury results denaturing of proteins. ( structural proteins and enzymes). • Anucleated cells persist for days (proteolysis blocked). • Leucocytes migrate to the site and digest the cells by enzymes. Debris removed by phagocytosis. wedge-shaped kidney infarct (yellow).
- 73. Coagulative necrosis • Necroticcells in the infarct show preserved cellular outlines (ghost outline) • Eosinophilic cytoplasm • loss of nuclei • Adjacent inflammatory infiltrate
- 74. Liquefactive necrosis • Tissuesin which the initial digestion of cells and tissues predominates, with loss of structure. • Transform the tissue into a liquid mass. ⮚ Necrosis due to bacterial infection - substances released by bacteria and by PMNs attracted to the area result in rapid dissolution of the tissue - i.e. pus ⮚ Brain - infarction of brain tissue is followed by rapid dissolution, resulting in a liquid-filled space - unknown reason? An infarct in the brain, showing dissolution of the tissue.
- 76. Caseous necrosis. • Appear‘cheese like’ • process starts as coagulative necrosis and the necrotic tissue is broken down. This results loss of the structure. • Seen in Tuberculosis and some fungal infections.
- 77. Microscopy- Tissue architecture completelylost. necrotic material appear as a pink granular substance. The area of necrosis enclosed by inflammatory cells
- 78. Fat necrosis Related tofatty tissues ⮚Enzymatic- Mesentric fat necrosis due to acute pancreatitis ⮚Non enzymatic- traumatic fat necrosis of breast
- 79. Fat necrosis In acutepancreatitis lipases released from the pancreas act on fatty tissues causing digestion of fat into the free fatty acids and glycerol. Free FA combine with calcium to foam calcium soaps which appear as firm white chalky masses.
- 80. Fibrinoid necrosis Micro- Loss ofnormal structure and replacement by bright pink necrotic material similar to fibrin. A type of connective tissue necrosis. seen in vessel walls during hypertension, autoimmune diseases
- 81. Gangrene Not a distinctivepattern of cell death. Gangrene - special type of coagulation necrosis - Gradual ischemia of distal extremities, esp. foot and leg - “dry” - black-brown, mummified appearance - “wet” - bacterial superinfection of the necrotic material (Liquefactive Necrosis)
- 82. Effects of necrosis Abnormalfunction Myocardium: Heart failure Brain : paralyze Bacterial infection gangrene Release contents within necrotic material Myocardial infarction -Creatinine kinase AST, ALT from hepatocytes Systemic effects: fever, leucocytosis Local effects: Eg Ulcers
- 83. Apoptosis • Programmed celldeath. • A distinctive morphological pattern of cell death. • Occur in single cells • An energy dependent process
- 84. Apoptosis • Definition Apoptosis isa pathway of cell death. It is induced by a tightly regulated suicide program. in this cells are destined to die due to activated intrinsic enzymes that degrade the cells’ own nuclear DNA and nuclear and cytoplasmic proteins.
- 85. Causes of apoptosis Physiologic conditions Duringembryogenesis Involution of hormone dependent tissues upon hormone deprivation Cell loss in proliferation of cell populations Elimination of cells which have served their purpose Elimination of self reactive lymphoctes Pathologic conditions DNA damage Accumulation of misfolded proteins Cell injury in infections. eg-viral In organ atrophy after duct obstruction Refer- examples for each of these conditions.
- 86. If apoptosis fail?? •Aberrant development • Tumour proliferation • Autoimmune diseases
- 87. Mechanisms of apoptosis. •There are two pathways of apoptosis. • They differ in their induction & regulation. • But both activate caspases. ⮚Mitochondrial pathway ⮚Death receptor pathway
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- 89. Mitochondrial (intrinsic)pathway of apoptosis •Cell viability is maintained by the induction of anti-apoptotic proteins such as BCL2 by survival signals. • These proteins maintain the integrity of mitochondrial membranes and prevent leakage of mitochondrial proteins. • Loss of survival signals, DNA damage, and other insults activate sensors that antagonize the anti-apoptotic proteins and activate the pro-apoptotic proteins BAX and BAK, which form channels in the mitochondrial membrane. • The subsequent leakage of cytochrome c and other proteins leads to caspase activation and apoptosis.
- 90. Death receptor (Extrinsicpathway) • Death receptor are surface molecules on many cells that trigger apoptosis.(type 1 TNF, Fas/CD95) • Fas Ligand (Fas L)is a membrane protein expressed on activated T lymphocytes. • When these lymphocytes bind to Fas receptor expressing targets(Fas- Fas L), recruit and activate caspases.
- 91. • Caspases activatenucleases that degrade DNA an nucleoproteins. • Caspases also degrade nuclear matrix and cytoskeleton. • Cause cell fragmentation • Apoptotic cells removed fast by phagocytosis.
- 92. Morphology Microscopy • Shrunken cells •Form cytoplasmic buds and apoptotic bodies(membrane bound vesicles of cytosol and organelles). • Chromatin condensed and aggregated. • No inflammatory response (because fragmented cells are quickly eliminated by phagocytosis). Apoptosis of an epidermal cell in an immune reaction. The cell is reduced in size and contains brightly eosinophilic cytoplasm and a condensed nucleus.
- 94. necrosis Apoptosis Stimuli Alwayspathological Physiological and pathological mechanisms Not Energy dependent process Energy dependent ATP depletion Membrane injury Free radical damage Gene activation Endonucleases, proteases Large groups of cells Single cells Histology Cell swelling Cells shrink Chromatin condense Apoptotic bodies form DNA breakdown Random/diffuse Intra nucleasomal Cell membrane Integrity is lost Integrity is maintained Tissue reaction Inflammation No inflammation Phagocytosis of apoptotic bodies
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