Cell injury, adaptation, and death fix


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Cell injury, adaptation, and death fix

  2. 2. Normal cell is in a steady state“Homeostasis”Change in Homeostasis due to stimuli -InjuryInjury - Reversible / IrreversibleAdaptation / cell death
  3. 3. CELLULAR ADAPTATION TO STRESSAdaptations are reversible changes in the number, size, phenotype, metaboliPhysiologic adaptations are responses of cells to normal stimulation by hormPathologic adaptations are responses to stress that allow cells to modulate th
  4. 4. Hypertrophyis an increase in the size of cells & consequently an increase in thesize of an organ.the enlargement is due to an increased synthesis of structural proteins & organellesOccurs when cells are incapable of dividing Types: a) physiologic b) pathologic Causes: a) increased functional demand b) hormonal stimulation
  5. 5. Physiologic Hypertrophy of the Uterus During Pregnancy Gravid Uterus Normal Uterus
  6. 6. Small spindle-shaped uterine Large, plump hypertrophiedsmooth muscle cells from a smooth muscle cells from anormal uterus gravid uterus
  7. 7. Heart hypertrophy in hypertens
  8. 8. Hyperplasiais an increase in the number of cells in an organ or tissuean adaptive response in cells capable of replicationa critical response of connective tissue cells in wound healing Types: a) physiologic hyperplasia 1) hormonal ex. Proliferation of glandular epithelium of the female breast at puberty & during pregnancy 2) compensatory – hyperplasia that occurs when a portionof a tissue is removed or diseased e.g. partial resection of a liver > mitotic activity 12 hours later b) pathologic hyperplasiaCaused by excessive hormonal or growth factor stimulation
  10. 10. Atrophy Shrinkage in the size of the cell by the loss of cell substanceResults from decreased protein synthesis and increased protein degradation in cellsIs accompanied in many situations by increased autophagy with resulting Increases in autophagic vacoules Causes:Decreased workloadLoss of innervationDiminished blood supplyInadequate nutritionLoss of endocrine stimulationAging (senile atrophy)
  11. 11. Atrophy of the brain in an Normal brain of a 25-year-old82-year-old man man
  13. 13. Metaplasiaa reversible change in which one adult cell type ( epithelial or mes is cellular adaptation whereby cells sensitive to a parti able to withstand the adverse environmentEpithelial metaplasia ExamplesSquamos change that occurs in the respiratory epithelium in habitVitamin A deficiencyChronic gastric reflux, the normal stratified squamos epithelium of
  14. 14. Schematic diagram of columnar to squamos epithelialB. Metaplastic transformation of esophageal epitheliumMesenchymal metaplasia Ex. Bone formed in soft tissue particularly in foci of injury
  17. 17. CELLULAR INJURYCell Injury- pertains to the sequence of events when cells have no adapTypes of Cell Injury1. Reversible Injury- injury that persists within certain limits, cells return2. Irreversible Injury- when the stimulus causing the injury persists and i a. necrosis b. apoptosis
  18. 18. Causes of Cell Injury1. Hypoxia Causes: a. Ischemia b. Inadequate oxygenation of the blood c. Reduction in the oxygen-carrying capacity of the blood2. Chemical Agents a. glucose, salt or oxygen b. poisons c. environmental toxins d. social “stimuli” e. therapeutic drugs3. Physical agents- trauma, extremes of temperature, radiation, electric shock, & sudden changes in atmospheric pressure4. Infectious agents
  19. 19. 5. Immunologic reactions Example: anaphylactic reaction to a foreign protein or a drug reaction to self antigens6. Genetic defects Examples are genetic malformations associated with Down Syndrome, sickle cell anemia & inborn errors of metabolism7. Nutritional Imbalances
  20. 20. MORPHOLOGY OF CELL AND TISSUE INJURYAll stresses & noxious influences exert their effects first at the moleculaCellular function is lost far before cell death occurs and the morphologicUltrastructural Changes of Reversible Cell injuryAlteration in plasma membrane reflecting disturbance in ion and v2. Mitochondrial changes3. Endoplasmic reticulum changes4. Nuclear alterations
  21. 21. PLASMA MEMBRANE ALTERATIONS Cellular swelling Formation of cytoplasmic blebs Blunting and distortion of microvilli Deterioration and loosening of intercellular attachments
  22. 22. Mithochondrial Changes Early it appears condensed as a r Followed by swelling due to ionic Amorphous densities which corre Finally, rupture of membrane follo
  23. 23. Endoplasmic Reticulum Changes Dilation Detachment of ribosomes and dissociation of polysomes with decreased protein synthesis Progressive fragmentation and formation of intracellular aggregates of myelin figures
  24. 24. Nuclear AlterationsDisaggregation ofgranular andfibrillar elements
  25. 25. Two Patterns of Morphologic Change Correlating toReversible Injury that can be recognized under the lightMicroscope: cellular swelling and fatty changeCellular Swelling Is the result of failure of energy-dependent ion pumps in the plasma membrane leading to an inability to maintain ionic & fluid homeostasis first manifestation of almost all forms of injury to cellsmicroscopically small, clear vacoules may be seen within the cytoplasmsometimes called hydropic change or vacoular degenerationswelling of cells is reversible
  26. 26. Hydropic degeneration: kidneyCloudy swelling & hydropic change reflect failure of membrane ion pumps, due to lack of ATP, allowing cells to accumulate fluid
  27. 27. Fatty Change* occurs in hypoxic injury & various forms of toxic( alcohol & halogenated hydrocarbons like chloroform ) or metabolic injury like diabetes mellitus & obesitymanifested by the appearance of lipid vacoules in the cytoplasmprincipally encountered in cells participating in and involved in fat metabolism e.g. hepatocytes & myocardial cellsalso reversible
  28. 28. Morphologic Alterations in Reversible Cell InjuryCell swellingFatty changePlasma membrane blebbing and loss of microvilliMitochondrial swellingDilation of the EREosinophilia (due to decreased cytoplasmic RNA)
  29. 29. NECROSISRefers to a series of changes that accompany cell death, largely resulting from the degradative action of enzymes on lethally injured cellsThe enzymes responsible for digestion of the cell are derived either from the: 1) Lysosomes of the dying cells themselves or from 2) lysosomes of leukocytes that are recruited as part of the inflammatory reaction to the dead cells
  30. 30. Morphologic alterations in NecrosisIncreased eosinophilia (pink staining from eosin dye)Myelin figures ( whorled phospholipid masses)Nuclear changes assume one of three patterns all due to breakdown of DNA & chromatin: 1) Karyolysis 2) Pyknosis characterized by nuclear shrinkage and increased basophila 3) Karyorrhexis – fragmentation and dissolutionBreakdown of plasma membrane and organellar MembranesLeakage and enzymatic digestion of cellular contents
  31. 31. Patterns of Tissue NecrosisCoagulative NecrosisA form of tissue necrosis in which the component cells aredead but the basic tissue architecture is preserved for at least several days It is characteristics of infarcts ( areas of ischemic necrosis) in all solid organs except the brain A wedge-shaped kidney Infarct (yellow) with preserva tion of the outlines
  32. 32. Liquefactive NecrosisSeen in focal bacterial or occassionally fungal infections because microbes stimulate the accumulation of Inflammatory cells and the enzymes of leukocytes digest ( “liquefy”) the tissueThis necrosis is characteristic of hypoxic death of cells witnin the CNSAssociated with suppurative inflammation (accumulation of pus)The areas undergoing necrosis are transformed into a Semi-solid consistency or state (liquid viscuous mass) Example: abcess
  33. 33. Liquefactive necrosis. An infarct in the brain, showingdissolution of tissue
  34. 34. Caseous Necrosis Encountered most often infoci of tuberculous infectionCharacterized by a cheesy yellow-white appearance of the area of necrosisIt is often enclosed within a distinctive inflammatory border A tuberculous lung with a large area of caseous necrosis containing yellow-white and cheesy debris
  35. 35. Fat NecrosisRefers to focal areas of fat destruction, typically resulting from release of activated pancreatic lipases into the substance of the pancreas and the peritoneal cavityOccurs in acute pancreatitis Fat necrosis in aqcute pancreatitis. The areas of white chalky deposits represent foci of fat necrosis with calcium soapformation (saponification) at sites of lipid breakdown in the mesentery
  36. 36. Fibrinoid necrosisA special form of necrosis usually seen in immune reactions involving blood vesselsThis pattern of necrosis is prominent when complexes of antigens and antibodies are deposited in the walls of ArteriesDeposits of these immune complexes together with fibrin that has leaked out of vessels result in a bright pink and amorphous appearance called fibrinoid” Fibrinoid necrosis in an artery in a patient with Polyarteritis Nodosa. The wall of the artery shows a circumferential bright pink area of necrosis with protein deposition and inflammation
  37. 37. Gangrenous Necrosis This is not a distinctive pattern of cell deathIt is usually applied to a limb, generally the lower leg, that has lost its blood supply involving multiple tissue layersTypes:Wet gangreneOccurs in naturally moist areas like mouth, bowels lungsCharacterized by numerous bacteriaDry gangrenebegins at the distal part of the limb due to ischemia and oftenoccurs in the toes and feet of elderly patients due to arteriosclerosisThis is mainly due to arterial occlusionThere is limited putrefaction and bacteria fail to survive
  38. 38. SUBCELLULAR RESPONSES TO INJURYAutophagyRefers to lysosomal digestion of the cells ownIt is thought to be a survival mechanism in times of nutrient deprivationOrganelles are enclosed in vacoules that fuse with lysosomes Heterophagy a cell usually a macrophage ingests substances from the outside for intracellular destruction
  39. 39. Hypertrophy of Smooth Endoplasmic ReticulumCells exposed to toxins that are metabolized in the SER show hypMitochondrial Alterations * alterations in size, number, shape & function Ex. Mitochondria assume extremely large & abnormal shapes ( Cellular hypertrophy > # of mitochondria in cells Atrophy < # of mitochondriaCytoskeletal Abnormalities some drugs & toxins interfere with the assembly & functions o accumulations of filaments
  40. 40. General Principles Relevant To Most Forms Of Cell Injury The cellular response to injurious stimuli depends on the type of injury, its duration, and its severity The consequences of an injurious stimulus depend on the type , status , adaptability , and genetic makeup of the injured cellCell injury results from functional & biochemical abnormalities in one or more of several essential cellular components The most important target of injurious stimuli are: 1) cell membrane integrity, critical to cellular ionic and osmotic homeostasis 2) mitochondrial, the site of adenosine triphosphate (ATP) generation 3) protein synthesis 4) integrity of the genetic apparatus 5) cytoskeleton
  41. 41. MECHANISMS OF CELL INJURY ATP depletion: failure of energy-dependent functions reversible Injury necrosisMitochondrial damage: ATP depletion failure of energy- dependent cellular functions ultimately necrosis; under some conditions, leakage of proteins that causes apoptosisInflux of calcium: activation of enzymes that damage cellular components and may also trigger apoptosisAccumulation of reactive oxygen species: covalent modifications of cellular proteins, lipids, nucleic acidsIncreased permeability of cellular membranes: may affect plasma membrane, lysosomal membranes, mitochondrial membranes; typically culminates in necrosisAccumulations of damaged DNA and misfolded proteins triggers apoptosis
  42. 42. Accumulation of Oxygen-Derived Free radicals (Oxidative Stress)Free radicals are chemical species with single unpaired electron in an outer orbital. In such a state the radicals are extremely unstable & readily react with inorganic or organic chemicals. Free radicals may be generated within cells byReduction-oxidation (redox) reactionsNitric oxide (NO)Absorption of radiant energy (e.g. ultraviolet light, x-rays)Enzymatic metabolism of exogenous chemicals (e.g. carbontetrachloride)Inflammation, because free radicals are produced by leukocytesthat enter tissues
  43. 43. Mechanisms that remove Free radicalsAction of superoxide dismutases (SODS)Glutathione (GSH) peroxidaseCatalase present in perixisomesEndogenous or exogenous antioxidants (e.g. vitamins E, A and C, and beta-Carotene may either block the formation of free radicals or scavenge them once they have formedIron and Copper can catalyze the formation of Reactive Oxygen Species (ROS)
  44. 44. APOPTOSIS (“FALLING OFF”)Is a pathway of cell death that is induced by a tightly regulated suicide program in which cells destined to die activate enzymes capable of degrading the cells own nuclear DNA and nuclear and cytoplasmic proteinsIt differs from necrosis in the following characteristics 1) Plasma membrane of the apoptotic cell remains intact 2) Has no leakage of cellular contents 3) Does not elicit an inflammatory reaction in the hostSometimes coexist with necrosisApoptosis induced by some pathologic stimuli may progress to necrosis
  45. 45. Causes of ApoptosisApoptosis in Physiologic Situations Death by apoptosis is a normal phenomenon thatserves to eliminate cells that are no longer needed and tomaintain a steady number of various cell populations in tissuesProgrammed destruction of cells during embryogenesis, Including implantation, organogenesis, developmental involution, and metamorphosisInvolution of hormone- dependent tissues upon hormone deprivation such as endometrial cell breakdown during the menstrual cycle and regeression of the lactating breast after WeaningCell loss in proliferating cell populations, such as intestinal Crypt epithelia
  46. 46. Death of cells that have served their useful purpose, such as neutrophils in an acute inflammatory response and Lymphocytes at the end of an immune responseElimination of potentially harmful self-reactive lymphocytes Either before or after they have completed their maturationCell death induced by cytotoxic T lymphocytes, a defense mechanism against viruses and tumors that serves to kill eliminate virus-infected and neoplastic cells
  47. 47. Apoptosis in Pathologic Situations Apoptosis eliminates cells that are genetically altered orInjured beyond repair without eliciting a severe host reaction,thus keeping the damage as contained as possible DNA damage Radiation, cytotoxic anticancer drugs, extremes of temperature and even hypoxia can damage DNA either directly or via production of free radicalsAccumulation of misfolded proteinsThese may arise because of mutations in the genes encoding these proteins or because of extrinsic factors such as free radicalsExcessive accumulation of these proteins in the ER leads to a condition called ER stress
  48. 48. Cell injury in certain infections particularly viral infectionsPathologic atrophy in parenchymal organs after duct obstruction such as in pancreas, parotid gland and kidneyMorphologic Alterations in ApoptosisNuclear chromatin condensationFormation of apoptotic bodies ( fragments of nuclei and cytoplasm)The fundamental event in apoptosis is the activation of enzymecalled caspases
  49. 49. Two Major Pathways in the Initiation of Apopotosis1) Mitochondrial ( intrinsic) pathway Triggered by loss of survival signals, DNA damage and accumulation of misfolded proteins (ER stress)2) Death receptor (extrinsic) pathway Responsible for the elimination of self-reactive lymphocytes and damage by cytotoxic T lymphocytes
  50. 50. INTRACELLULAR ACCUMULATIONSTHREE MAIN PATHWAYS OF ABNORMAL INTRACELLULARACCUMULATIONSA normal substance is produced at abnormal or an increased rate, but metabolic rate is inadequate to remove it Example. Fatty change in the liverA normal or abnormal endogenous substance accumulates because of genetic or acquired defects in its folding, packaging, transport or secretion Example. Accumulation of of proteins in anti-trypsin deficiencyAn abnormal exogenous substance is deposited and Accumulates because the cell has neither the enzymatic Machinery to degrade the substance nor the ability to transport It to other sites. Example. Accumulation of carbon or silica particles
  51. 51. Fatty Change (Steatosis)Refers to any abnormal accumulation of triglycerides within parenchymal cellsMost often seen in the liver but may also occur in the heart, Skeletal muscle, kidney and other organsMay be caused by toxins, protein malnutrition, diabetes mellitus, obesity and anoxiaAlcohol abuse and diabetes associated with obesity are the most common causes of fatty liver
  52. 52. Fatty Liver
  53. 53. Cholesterol and Cholesteryl EstersResult of defective catabolism and excessive intakePresent in lipid vacoules of smooth muscle cells and macrophages in atherosclerosis (hardening of the aorta)Give atherosclerotic plaques their characteristic yellow color and contibute to the pathogenesis of the lesionXanthomas are hypercholesterolemic tumurous masses found in the connective tissue of the skin or tendons
  54. 54. ProteinsLess common than lipid accumulationsOccur because excess are presented to the cells or because the cells synthesize excessive amountsExamples: 1) Nephrotic syndrome there is heavy protein leakage across the glomerular filter due to a much larger reabsorption of albumin 2) accumulation of newly synthesized imunoglobulins in RER of some plasma cells forming rounded, eosinophilic Russell bodies 3) Mallory body or “ alcoholic hyalin” is an eosinophilic cytoplasmic inclusion in liver cells highly characteristic of alcoholic liver disease 4) Neurofibrillary tangle found in the brain in Alzheimer disease
  55. 55. Protein reabsorption droplets in the renal tubular epithelium
  56. 56. GlycogenAccumulations of these are associated with abnormalities in the metabolism of either glucose or glycogenEx. 1) In poorly controlled diabetes mellitus, glycogen accumulates in renal tubular epithelium, cardiac myocytes, and β cells of Islets of langerhans 2) Glycogen storage diseases or glycogeneses are Genetic disorders where glycogen accumulates in macrophages of patients with defects in lysosomal enzymes
  57. 57. Pigmentscolored substances that are either exogenous or endogenousExogenous – coming from outside the body 1) Carbon ( ex. Coal dust)Most common air pollutantAggregates of the pigment blacken the draining lymph nodes and pulmonary parenchyma (Anthracosis)Heavy accumulations may induce emphysema or a fibroblastic reaction that can result in a serious lung disease called coal workers pneumoconiosis
  58. 58. Endogenous – synthesized within the body itself 1) Lipofuscin or “wear-and -tear pigment or lipochromean insoluble brownish-yellow granular intracellular material that accumulates in the heart, liver, & brain as a function of age or atrophyrepresents complexes of lipid & protein that derive from the free radical-catalyzed peroxidation of polyunsaturated lipidsit is not injurious to the cell but is important as a marker of past free-radical injurythe brown pigment when present in large amounts, imparts an appearance to the tissue that is called brown atrophy
  59. 59. The pale golden brown finely granular pigment seen here in nearlyall hepatocytes is lipochrome (lipofuscin).
  60. 60. 2) MelaninAn endogenous, brown-black pigment synthesized exclusively by melanocytes when the enzyme tyrosinase catalyzes tyrosine to (DOPA) dihydroxyphenylalanine located in the epidermisActs as a screen against harmful ultraviolet radiationBasal keratinocytes in the skin can accumulate the pigment (e.g. in freckles)
  61. 61. Melanin pigment in melanoma
  62. 62. 3) Hemosiderin A hemoglobin-derived granular pigment that is golden yellow to brown and accumulates in tissues when there is a local or systemic excess of ironIron is normally stored within cells in association with the protein apoferritin, forming ferritin micellesIron can be identified by the Prussian blue reaction
  63. 63. Local excess of iron & consequently of hemosiderin result from hemorrhage Ex. Bruise The original red-blue color of hemoglobin is transformed to varying shades of green-blue by the local formation of biliverdin (green bile) and bilirubin (red bile) from the heme moietyThe iron of hemoglobin accumulate as golden- yellow hemosiderin
  64. 64. Hemosiderosisa condition where hemosiderin is deposited in many organs and tissues whenever there is systemic overload of ironIt occurs in the following settingsIncreased absorption of dietary ironImpaired utilization of ironHemolytic anemiasTransfusions Hereditary HemochromatosisA condition where there is extensive accumulations of iron with tissue injury like liver fibrosis, heart failure and diabetes mellitusCharacterized principally by 1) the deposition of hemosiderin in the following organs (in decreasing order of severity):liver, pancreas, myocardium, pituitary, adrenal, thyroid, joints & skin 2) cirrhosis and 3) pancreatic fibrosis
  65. 65. PATHOLOGIC CALCIFICATIONimplies the abnormal deposition of calcium salts, together with small amounts of iron, magnesium, and other mineralsTYPESA. Dystrophic calcificationdeposition of calcium in dead or dying tissuesoccurs in the absence of calcium metabolic derangements ( with normal serum levels of calcium)Local deposits of calcium may occur in 1) necrotic tissue which is not absorbedold infarctstuberculous fociold collection of pusdead parasitesacute pancreatic necrosis
  66. 66. 2) Tissue undergoing slow degenerationHyaline areas in benign tumorsFibroidsIn arteries due to atheromatous degeneration or old ageOld thrombiDiseased or abnormal heart valvesPathogenesisInitiation ( or nucleation)Propagation Both may be intracellular or extracellular with calciumphosphate as the end product
  67. 67. B. Metastatic Calcification deposition of calcium salts in normal tissuesalmost always reflects some derangement in calcium metabolism ( hypercalcemia)Four major causes of hypercalcemia1) Increased secretion of parathyroid hormone, due to either parathyroid tumors or production of parathyroid hormone- Related protein by other malignant tumors2) Destruction of bone due to the effects of accelerated turnover (e.g. Paget disease),immobilization, or tumors (increased bone catabolism associated with multiple myeloma, leukemia or diffuse skeletal metastases)3) Vitamin D-related disorders like vitamin D intoxication and sarcoidosis ( in which macrophages activate a vitamin D precursor4) Renal failure, in which phosphate retention leads to secondary hyperparathyroidism
  68. 68. CELLULAR AGINGresults from combination of accumulating cellular damage (e.g., by free radicals), reduced capacity to divide (replicative senescence), and reduced ability to repair damaged DNACellular senescenceAging of a person is intimately related to cellular agingMechanisms known or suspected to be responsible for cellularagingDNA damagedefective DNA repair mechanisms DNA repair may be activated by calorie restriction (known to prolong aging in model organisms)
  69. 69. Replicative senescenceReduced capacity of cells to divide because of decreasing amounts of telomerase and progressive shortening of chromosomal ends (telomeres) Telomeresare short repeated sequences of DNA present at the linear ends of chromosomesImportance * for ensuring the complete replication of chromosome ends * and for protecting the ends from fusion & degradationProgressive accumulation of metabolic damageRepeated environmental exposure to radiationProgressive reduction of antioxidant defense mechanism Like Vit. E & glutathione peroxidasePossible roles of growth factors
  70. 70. Telomerase in Ageing:GermcellsSomaticcells
  71. 71. WERNER SYNDROMEA rare disease characterized by premature aging