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Cell injury pathology revision notes
The document discusses various topics related to pathology including causes of cell injury, hypoxia, cellular adaptive responses, mechanisms of cell injury, features of reversible and irreversible injury, necrosis, apoptosis, calcification, pigmentation, and cellular aging. The key points are: 1. Hypoxia is the most common cause of cell injury, usually due to ischemia. Neurons are the most susceptible tissue to hypoxic damage. 2. Cellular adaptive responses to injury include atrophy, hypertrophy, hyperplasia, metaplasia, dysplasia. 3. Apoptosis is an active and programmed form of cell death, while necrosis is unprogrammed cell death due to severe injury
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Cell injury pathology revision notes
- 1.
- 2. Causes of Cellinjury • Hypoxia • Most common cause of cell injury • Ischemia mc cause of hypoxia • Physical agents • Chemical agents • Infections • Immunological agents • Genetic cause • Nutritional imbalance
- 3. Hypoxia • Neurons • Mostsusceptible tissue to ischemia • Irreversible damage with in 3 to 4 minutes • Myocardial cells • Irreversible damage with in 20 to 30 minutes • Fibroblast • Most resistant to ischemic damage
- 8. Cellular adaptive responseto injury • Atrophy • Hypertrophy • Hyperplasia • Atrophy • Metaplasia • Dysplasia
- 9. Hyperplasia • Increase innumber of cells • Hyperplasia is absent in heart brain & skeletal muscle • Physiologic • Compensatory : after hepatectomy • Hormonal : breast @ puberty • Antigenic stimulation : lymphoid hyperplasia • Pathologic • Mediated by GF cytokines / increased expression of proto- oncogenesincreased DNA synthesis & cell division
- 10. Hypertrophy • Increase insize of cells in nondividing cells • d/t induction of genes increased transcription /GF/vasoactive agents increased syn of intracellular components • Increased mechanical demand • Physiological • Skeletal muscle • Pathological • Increased endocrine stimulation • Lactating breast
- 11. • Hyperplasia &hypertrophy occur together • in gravid uterus • Mainly hypertrophy + only some hyperplasia • In breast during puberta period & pregnancy
- 12. Atrophy • Decrease incell size & functional ability • Causes • Decreased work load/disuse • Loss of blood / nerve /hormonal stimulation • Malnutrition • Ageing • Pressure • Small shrunken cells with lipfuchsin granules brown atrophy • DECREASED PROTEIN SYNTHEISS • Increased protein degradation • In lysosomes • Ubiquitin –proteasome pathway • Autophagic vacuoles d/t decreased nutrition
- 14. Metaplasia • Reversible changeof one cell type by another in response to irritation • d/t tissue specific & differentiation genes reprogramming of stem cells • Squamous metaplasia • In respiratory epithelium in smokers • Columnar metaplasia • In baretts esophagus
- 15. • Vitamin Adeficiency or excess metaplasia • Deficiency squamous metaplasia in respiratory epithelium
- 16. Baretts esophagus • Intestinalmetaplasia (d/t presence of goblet cells ) • Increased risk of endometrial adenocarcinoma
- 17. DysplasiaNOT A CELLULARADAPTATION • An abnormal proliferation of cells • Increase in size shape & loss of cellular organisation • Intact basement membrane • Not malignancy but nay progess to malignancy
- 19. Mechanism of cellinjury
- 22. Effect of influxof Ca2+
- 23.
- 24.
- 26. Features of reversibleinjury • Cellular swelling • First manifestation of all cell injury • Except for apoptosis in which cell shrinkage is seen • Hydropic degeration /cloudy swelling • Intacellular water accumulation
- 29.
- 31. Hypoxia earliestinvolvement of mitochondria inhibit oxidative phosphorylation
- 32. Myelin figures areseen in cell inury • Whorls of laminates PL & Ca2+ • More promineny in necrosis than in reversible cell injury • Break down of membrane organelles composed of phospholipids
- 33. Light microscopic changesin reversible injury • Irregular swelling /cloudy swelling/hydropic change • Prominent in kidney • Earliest • Fatty changes • In cells involved in fat metabolism • In hepatocytes & myocardial cells
- 34. Irreversible cell injury •Severe membrane damage • Masive influx of ca2+ • Efflux of intracellular enzymes in to circulation • Marked mitochondrial dysfunction
- 38. • CELLS MOSTSENSITIVE TO HYPOXIA NEURONS • ESP PYRAMIDAL CELLS IN HIPPOCAMPUS
- 39. Stepladder pattern d/tendonuclease induced internucleosomal damage in apoptosis Diffuse smearing in necrosis
- 40. Cytoplasmic changes innecrosis • Increased eosinophilia • d/t protein denaturation • Glassy appearance d/t loss of glycogen • Cytoplasm is vacuolated moth eaten • D/T ENZYMATIC DIGESTION VACOULE APPEAR • Finally calcification
- 41. Nuclear changes innecrosis
- 42. Nuclear changes innecrosis • Pyknosis • Nuclear shrinkage • Chromatin condensation • Karyorhexis • Nuclear fragmentation • Karyolysis • Decrease basinophilia • d/t dissolution of chromatin
- 43. Types of necrosis •Coagulative • Liquefactive • Caseous • Fat • Fibrinoid necrosis • Gangrenous necrosis
- 44. Coagulative necrosis • Mostcommon type • Architecture of tissue preserved • Ghost cell outline /tomb stone • Cellular outline is maintained • Loss of nucleus • a/w ischemia (hypoxia) • d/t denaturation of protein • Seen in all tissues (heart***(mc) liver kidney) • except brain LIQUEFACTIVE • Zenkers degeration necrosis • Waxy hyaline degenerstion of skeletal muscle in a/c infectious ds
- 45. Liquefactive necrosis • Seenin • focal bacterial • Most common cause • ischemia in brain • d/t local stromal support & abundant liquefactive necrosis • occasionally fungal infections • d/t enzymatic degradation • Inflammatory cells –> hydrolytic enzymes tissue degradation into liquid viscuous mass no cellular details
- 46. Caseous necrosis • Combinationof liquefactive & coagulative necrosis • d/t mycolic acid of TB • Friable cottage cheese like reaction • Characteristic feature of TB • Unlike coagulative necrosis • Tissue architecture is completely obliterated
- 48. • If caseationis absent & lymphoid infiltrate is absent • In naked granuloma sarcoidosis
- 49. Fat necrosis • d/tlipases on fatty tissue • Seen in breast omentum pancreatitis • Chalky white in appearance
- 50. Fibrinoid necrosis • Immunereactions involving blood vessels • Complexes of Ag & Ab around blood vessel with leakage of fibrinogen • bright pink amorphous densities • Seen in • PAN • Malignant hypertension • Immune complex vasculitis
- 51. Fibrinoid necrosis isseen in
- 52. Gangrenous necrosis • Drygangrene • Microscopic pattern of coagualative • POVD • wet gangrene • Microscopic pattern of liquefactive necrosis • Superadded putrefaction • Bowel mouth vulva cervix • Gas gangrene • Cl perfringens • P/S poikilocytoses(spherocytes)
- 53.
- 55. Necrosis Apoptosis Increase incell size Decrease in cell size Pyknosis karyorrhexis karyolysis Nuclesome Membrane damage Intact membrane
- 56. Apoptosis • Active process(energy dependent process d/t involvement of mitochondria) • Programmed cell death
- 57. Physiological • Embryogenesis organogenesis neovascularisation •Hormone dependent involution of tissues • Cell death after completion of its function Pathological • Accumaltion of misfolded protein • Duct obstruction • Cytotoxic CTx / Rtx
- 58. Morphological features Most characteristicfeature Earliest feature
- 59.
- 60. Biochemical features ofapoptosis • Protein cleavage by caspases • DNA break down by endonuclease • 50 – 300 kbp size step ladder pattern in agarose gel electrophoresis
- 61. Caspases • Proteases withcysteine group
- 62. Annexin V isa marker of apoptosis • Flipping of phosphatidyl serine from inside to outside allow recognition of apoptotic cells
- 64. Regulation of apoptosis •Bcl-2 • Located on mitochondrial membrane • Inhibit apoptosis • Bcl – xL lower apoptosis • Bak bax bim • Stimulate apoptosis • Bcl – Xs (S- stimulate apoptosis )
- 69. Mechanism of apoptosis •Initiation • Activate initiator caspases • 2 pathways • Intrinsic (mitochondrial) • Extrinsic (death receptor pathway) • Execution • Activate caspase 3 *** /6/7 (executioner caspases )
- 70. • Glucocorticoids stimulate apoptosis • Hence used in Rx of leukemia /lymphoma/myeloma • Sex steroids inhibit apoptosis
- 73. Intrinsic pathway Wheel likehexamer (apoptosome) activation of caspase 9
- 75.
- 76. Extrinsic pathway • TRAIL •TNF related apoptosis inducing ligand binds to DR4 & 5 Caspase 10 in humans
- 79.
- 80. CD 95 CD 95 ismolecular marker of apoptosis
- 84. Diagnosis of apoptosis •1. Chromatin condensation seen by hematoxylin, Feulgen and acridine orange staining. • 2.Estimation of cytochrome ‘c’ • 3. Estimation of activated caspase • Caged flurophores , FRET • 4. Estimation of Annexin V • 5. DNA breakdown at specifc sites can be detected by ‘step ladder pattern’ on gel electrophoresis or • 6.TUNEL (TdT mediated d-UTP Nick End Labelling) technique. • Terminal transferase
- 86. Necroptosis • Hybrid ofnecrosis + apoptosis • Programmed cell death with out caspase activation • Cell swelling • Increased lysosomal permeability • Cell membrane damage • Presence of inflammation
- 87. Pyroptosis • Neither necrosisnor apoptosis • Caspase dependent (caspase 1 & 11 ) programmed cell death • Cell swelling • Cell membrane damage • Presence of inflammation • Caspase 1 & caspase 11 involved
- 88. Free radical • Singleunpaired electron in outer orbit • Reactive oxygen species • Normally produced as an unavoidable by product of mitochondrial respiration
- 93.
- 95. Fenton reaction Fe2+is converted to Fe3+
- 96. Subcellular response toinjury • Autophagocytosis • Lysosomal digestion of cells own components • Digest protein CHO except lipids • Cell eats its own components • In nutrient deprivation • In atrophy • Autophagosome + • Autophagolysosome+
- 97. Deletion of Atg5increased susceptibility to tuberculosis • Atg5 autophagy related genes
- 99. Heterophagy • Cells ingestsubstances from outside for intracellular digestion • Induction of SERhypertrophy of SER • On phenobarbitone therapy hypertrophy of SER
- 100. Ischemia reperfusion injury •In cerebral/myocardial ischemia • Recruitment of WBC inflammation + generation of free radicals
- 101. Reperfusion injury • Appearsas contraction bands after MI
- 102.
- 103. Lipids • Intracellular lipidaccumulation steatosis • Mainly in liver • Triglyceride ***(mc) • Cholestrol &CE • PL • Tigeroid / tabby cat myocardial cells • Alternating bands of dark red normal myocardium with yellow streaks • d/t lipid accumaltion • Special stains • Oil red O stain • Sudan black B • Sudan IV • Osmium tetroxide
- 104. Proteins • In proteinuriaProtein accumalates in proximal renal tubule • Russel bodies • Intracytoplasmic accumaltion of Ig • Defective protein folding accumulation • Alzheimers d/s /parkinsons ds/huntingtons ds Russel bodies
- 105. Chaperones • Chaperones inthe ER control proper folding of newly synthesised proteins
- 108. Pigments • Exogenous • Tattooingwith india ink /cinnbar • Carbon in lungs • Endogenous • Lipofuschin • Melanin • Haemosiderin
- 109. Lipofuschin pigment • Wear& tear pigment • Telltale sign of free radical injury • From indigested material from radical mediated lipid peroxidation • Perinuclear brown pigment • Composed of lipids & PL in combn with proteins • Cellular atrophy • Brown atrophy of myocardium
- 111. Melanin • Only endogenousbrown black pigment • In melanocytes & substantia nigra • Detected by fontanna masson staining
- 112. Hemosiderin • Golden yellowbrown pigment • Granular intracellular pigment composed of aggregated ferritin micelles • In areas of haemorrhages & bruises / systemic iron overload • Detected by perl’s Prussian blue reaction
- 113.
- 114. Pathologic calcification • Abnormaldeposition of Ca2+ along with small amounts of mg2+ & fe2+ • Starts • In mitochondria or microsomal vesicles • In basement mebrane in kidney • Stains for Ca2+ • VON – KOSSA (BEST) • ALIZARIN RED-S • Calcein stain • Tetracycline labelling index (best method to detect bone demineralisation) • 2 types • Dystrophic • Metastatic
- 115. Dystrophic • Dead /degenerated tissue • Serum Ca2+ is normal • Psammoma bodies • In meningioma/papillary CA thyroid/mesothelioma/serous cystadenoma of ovary • Monckebergs medial calcific stenosis • Tuberculous LN (caseous necrosis) • Atherosclerosis • Fat necrosis
- 116. Metastatic • Raised Ca2+ calcification in normal tissues • Causes • Hyperparathyroidism *** • **Parathyroid adenoma *** • Vitamin A toxicity • Vitamin A activates osteoclast increased bone resorption & hypercalcemia • Milk alkali syndrome • Renal failure • Vitamin D related disorders • Vitamin D intoxication • Williams syndrome (idiopathic hypercalcemia of infancy) • Sarcoidosis • Saracoid gramuloma synthesise excess 1,25 OH vitamin D3
- 117. Metastatic calcification • Mostcoomon site • Lung alveoli • Systemic arteries & pulmonary V • Gastric mucosa • Cornea & conjunctiva
- 118. Glycogen storage ds •Best carmine or PAS with diastase sensitivity • Best fixative is alcohol
- 119. Hyaline change • Pinkhomogeneous appearance • Intracellular • Mallory alcoholic hyaline • Russel bodies • Zenkers degeneration • Extracellular • Hyaline memb in newborn • Corpora amylacea in brain prostate • Hyaline arteriosclerosis
- 120. Cellular aging • Mostwidely used theory • Free radical mediated damage
- 121. Telomeres • Short stretchesof DNA @ end of chromosomes • Important in ensuring complete replication of chromosomes & protects chromosomal ends from fusion & degradation
- 122. Telomerase shortening • Progressivetelomerase shortening limit cell division to 60 to 70 times cellular senescence
- 123. Telomerase • Aare reversetranscriptases or RNA dependent polymerase • Normally present in germ cells >> stem cells • Presence in normal somatic cells neoplastic transformation
- 126. WERNER SYNDROME • Adefect in DNA helicase enzyme • required for DNA replication and repair results in premature ageing
- 127. sirtuin • Plays animportant role in aging / DM & various cancers • NAD dependant deacetylase • Stimulates protein folding • Decrease apoptosis • Inhibit free radical damage • Increase insulin sensitivity
- 130. • Commonest fixative •In light microscopy 10 % bufferd formalin • In e microscopy glutaraldehyde
- 132. megamitochondria • ALD • Steatohepatitits •Mitochondrial myopathies • oncocytoma
- 133. Zenkers degeneration • Truecoagulative necrosis • Affecting skeletal muscles >>> cardiac muscles • Rectus diaphragm • During a/c infections typhoid
- 134. Oncocytes • Epithelial cellsstuffed with mitochondria imparts granular appearance to cytoplasm • Granular pinkish • Abundant megamitochondria • Seen in • Thyroid • Hurtle cells • Parathyroid • Lung & pituitary • pancreas • Salivary gland • Kidney
- 135. Oncocytoma • Benign tumrwith oncocytic cells • In thyroid kidney & salivary gland • Renal oncocytoma • Mahagoni brown colour with central scar
- 136. Councilman bodies Hepatitis Gamnagandy bodies Congestive splenomegaly calcific deposits admixed with haemosiderin on fibrous tissue Negri bodies Rabies Negri bodies are distributed throughout the brain, particularly • Most commonly in hippocampus • in Ammon's horn, the cerebral cortex, the brainstem, the hypothalamus, the Purkinje cells of the cerebellum, and the dorsal spinal ganglia Lewy body Parkinsons disease Hirano bodies Alzheimers ds Asteroid bodies Sarcoidosis Aschoff bodies Rheumatic heart ds Verocay bodies Schwannoma Cal exner bodies Granulosa
- 137. Cytoskeleton • Actin • Thinnest •Intermediate filaments • Myosin • Microtubule • Thickest
- 138. Intermediate filaments • Detectedby immunohistochemistry • Shows Histogenesis / origin of malignancy • Desmin • In skeletal muscle tumour /rhabdomyosarcoma • Cytokeratin • Epithelial tumours / carcinoma • Dysmentin • Sarcoma • Melanoma • HMB 45 • Lymphoma • LCA /CD 45
- 139. Defect in microtubularfn • Vinca alkaloids • Colchicine in gout • Kartageners syndrome • Cystic fibrosis
- 140.
- 141.
- 144. Howell jolly bodies •Splenectomy • Hyposplenism • Megaloblastic anemia • Hemolytic anemia
- 145. Cabots ring • thin- darkly-stained ring that follows the margin of the red cell • In the form of partial loops, loops, or figure eights • granules in a linear array rather than as complete rings
- 146.
- 147.
- 150.