Flexner – pathology is ultra important

Bichat – importance of dissection/autopsy

Virchow – father modern pathology

- importance of studying cells

4 disease aspects

- etiology = cause

- pathogenesis = mechanism

- morphologic change

- clinical significance = signs/symp

Adaptations

  1. atrophy – decrease SIZE/function of cell
  2. caused by: dec workload, loss innervation, low blood, bad nutrition, loss trophic stimulation, aging
  3. hypertrophy – increase SIZE/function cell
  4. caused by: inc demand in tissues unable of cell division (musc, etc) due to physiological (inc exercise, uterus during pregnancy) or patho (left ventricular hypertension) reasons
  5. inc size due to inc cell proteins and organelles
  6. hyperplasia – inc NUMBER of cells due to physio (hormonal, compensatory) or patho (excessive hormone/growth factor) – also inc size/func of organ/tis
  7. thyroid hyperplasia = graves disease
  8. panhypopituitaryism (Sheehan syndrome) = inc pres on pit gland causes death of gland
  9. protooncogenes – code for cell death/division
  10. bone marrow response to hemorrhage, repair broken bones (fracture callus), benign prostatic hyperplasia
  11. metaplasia – adult cell changes to different cell type (reversible)
  12. caused by chronic irritation/inflammation/stress to cell
  13. Barrett’s esophagus) – ciliated columnar change to squam epithelium
  14. precursor to cancer (as are most chronic inj cells)
  15. bladder – trans epith change to squam due to chronic infection/irrit
  16. modifying metabolism – fatty acid mobilization, osteoclast stim (via parathyroid hormone), hepatic enzymes for drug metab

Cell Stress Response – reduce coding for normal/structural prots (housekeeping)…inc prod for organizing/protective prots (cell stress genes aka heat shock proteins)

- HSPs label shit from cell to be removed (old junk and extra mitochon, ER, etc)

- ubiquitin binds shit to form “inclusion bodies” aka “Mallory’s hyaline” (pink from liver alcoholism) aka “Lewy body” in neural cells

- ubiquitin acts as cofactor for proteolysis (removal prots)

CELL INJURY – occurs to membrane, mito, cytoskeleton, DNA

-injury to 1 results in 2ndary injury to others

-ischemia/hypoxia, free radicals, viruses, chemicals

Mechanisms of Cell Injury

  1. ischemia/hypoxia/apoxia
  2. isc = red bl sup LEADS TO hyp = O2 deficiency
  3. hyp causes red ATP prod > depletes cellular ATP > failure Na/K and Ca pumps > K leaves, Na, H20, Ca enter > cell swelling, loss of microvilli, blebs, ER swelling, myelin figures
  4. increase Calcium cases activation of:
  5. protein kinases – phosphorylate prots
  6. ATPase – dec ATP
  7. Phospholipases – membrane damage
  8. Endonuclease – nuc chromatin damage
  9. Proteases – cytoskel/mem damage
  10. Depleting ATP > stim phosphofructokinase > + glycolysis > + lactic acid/-ph >
  11. Clumping of chromatin, release of lysosomal enzymes >
  12. detach ribosomes from RER
  13. dec prot synth
  14. degrade cytoplasmic/nuc components > damage mem
  15. cell death
  16. FREE RADICALS – formed by absorption of radiant energy, redox rxns during respiration (mito), metab of drugs & exogenous chem., intracell odidase rxns (xanthine), oxygen therapy, neutrophils
  17. Most important are reactive oxygen species
  18. Superoxide anion
  19. Hydroxyl radical
  20. Hydrogen peroxide
  21. Innate defenses to above
  22. Superoxidase dismutase, glutathione peroxidase, catalases, antioxidants (vit E)
  23. Damagine Effects
  24. Peroxidation of lipids > mem damage
  25. Thiol containing prot damage > ion pump damage
  26. DNA damage > impaired prot synth
  27. Mito damage > Ca influx
  28. Re-Perfusion Necrosis – blood supply re-established causing huge amounts of reactive oxy spp to be generated by mito and xanthine oxidase
  29. Xanthine oxidase – oxidizes xanthine to generate reactive oxy spp
  30. Iron – Fe3+ is normally reduced by superoxide anions to Fe2+
  31. FENTON RXN: h2o2 rxn w/ Fe2+ to prod hydroxyl radical
  32. Innate mechanisms unable to protect and cell damage/death occurs
  33. Cause injury by lipid peroxidation of mem, damaging DNA, damaging prot structure by cross linking sulhydryl groups
  34. Pen is small
  35. VIRUSES
  36. Directly cytopathic – pore in mem > chem. Equil > cell death
  37. Polio (ssRNA)
  38. Genome translated into prot, embeds in mem, forms pore
  39. Indirectly cytopathic – DNA transcribed into mRNA, then prot by host’s RNA polymerase
  40. Hep B (dsDNA)
  41. Viral prot plugs pore, Tcell recognizes as foreign > T cell disrupts hosts mem integ > cell death
  42. CHEMICAL
  43. Directly cytopathic – chem act directly w/ organelle to cause death
  44. Heavy metals (Hg, Pb)
  45. mercury – binds to sulfhydryl > inhib ATPase dependent transport > inc mem permeability > death
  46. indirectly cytopathic – only toxic when body metabolizes them
  47. hepatotoxins
  48. CCL4 and acetaminophen
  49. Metab by P450 oxidase located in liver ER
  50. Cause mem damage via perox of mem phoslips
  51. Metab produces free radicals

Reversible Injury

  1. Swelling – 1st change recognized in almost all injuries
  2. Mem damage = loss of ability to maintain fluid homeo
  3. Aka hydropic change aka cloudy swelling aka vacuolar degen (from development of small intracellular vacuoles)
  4. Fatty Change – caused by metabolic derangement of injured cells normally handling lipids – usually seen in liver – 4 mechanisms
  5. Inc FFA mobilization – diabetes mellitus
  6. Inc conversion of FA into TAG – alcohol
  7. Red oxidation of TAGs into ACA – hypoxia, alcohol
  8. Deficiency of lipid acceptor prot (apoproteins) preventing export of formed TAGs – genetic disease, prot malnutrition

Lethal Injury : Necrosis = enzymatic dig of cell + denaturation of prots

  1. 2 types of enz digestion
  2. autolysis = intrinsic enz
  3. changes in cyto and nuc
  4. heterolysis = enz from other cells
  5. early necrotic cell
  6. inc cyto eosinophilia due to loss of cytoRNA
  7. pyknosis = nuc becomes small w/ inc basophils
  8. indicates that DNA transcription has ceased
  9. karyorrhexis = fragmentation of nuc
  10. karylolysis = complete dissolution of nuc
  11. TYPES OF NECROSIS
  12. Coagulative – dead tissue appearing FIRM and PALE – most common
  13. Preservation of structural outline of coagulated cells
  14. due to injury that denatures structural prots AND enzymatic prots, preventing protolysis
  15. characteristic of hypoxic cell death (except in brain)
  16. Liquefactive aka Colliquative – dead tis appears semiliquid
  17. Dissolution of tis by hydrolytic enz
  18. Necrosis in brain due to arterial occlusion (i.e. cerebral infarct/necrosis due to bacterial inf)
  19. Also occurs in infections
  20. Gangrenous
  21. Combo of coagulative w/ superimposed infection with liquefactive
  22. Called “wet gangrene”
  23. Casseous – dead tis is soft and white (like cream cheese)
  24. Dead cells form amorphous proteinaceous mass, but no original architecture is present (as it was in coagulative)
  25. As seen in tuberculosis
  26. Gummatous – dead tis is firm and rubbery
  27. Dead cells form amorphous proteinaceous mass w/ no original architecture (same as casseous)
  28. Only used to describe syphilis
  29. Hemorrhagic – dead tis w/ extravasated red cells
  30. Occurs when cell death is due to venous blockage
  31. Fat – chalky white areas
  32. Occurs when pancreatic enz released into peritoneal cavity during acute pancreatitis
  33. Enz liquefy fat cell mem and hydrolyze TAGs
  34. released FA combing w/ Ca to prod chalky, white areas
  35. also seen after trauma to fat i.e. breast injury
  36. Fibrinoid – fibrin deposits in necrotic vessel wall due to vasculitis and hypertension

Apoptosis – intentional, normal cell death by synthesis/activation of cytosolic proteases

  1. Examples
  2. Destruction of cells during embryogenesis
  3. implantation
  4. Hormonal-dependent physiological involution
  5. Endometrium during menstruation, breast after weaning, prostate after castration
  6. Cell depletion in proliferating populations
  7. Intestinal crypt epithelium
  8. Cell death in tumors
  9. Depletion of immune T cell populations
  10. Involution – physiological organ atrophy via apoptosis
  11. Stages
  12. Priming - Enz for apop synthesized
  13. Once primed cell only survives if “saved” by trophic factor (bcl-2)
  14. Cell surface specializations lost
  15. Nuc chromatin condenses (organelles remain normal)
  16. Endonucleases cleave chromosomes into indiv nucleosome frags
  17. Apoptic bodies – cell split into fragments (each containing good organelles and mito)
  18. Neighboring cells phagocytize frags

Subcellular Responses to Injury

  1. Cytoskeletal Abnormalities (cytoskel = microtubules, thin actin, thick mysosin)
  2. Reflected by defects in motion/organelle movements and sometimes accumulation of fibrillar material
  3. Microtubule Defects
  4. Chediak-Higashi syndrome = defect in microtubule polymerization giving leukocytes difficulty phago bacteria
  5. Male sterility – can be caused by microtubule org defect preventing sperm motility
  6. Bronchiectasis – microtub defect immobilizing cilia
  7. Intermediate filament defects
  8. Mallory body – accumulation of intermed fil in alcoholic liver
  9. Lysosomal Abnormalities – lyso contain hydrolytic enz synth in RER and packaged in golgi (called primary lysosomes)
  10. 2ndary lyso = primary lyso that is fused with phagosome
  11. break down phago material in 2 ways
  12. heterophagy – most common in neutrophils and macrophages
  13. handles shit taken up by endo/pino cytosis
  14. phagocytosis of bacteria/apoptitic cells
  15. autophagy – involves intracellular organelles/cytosol
  16. stuff packaged into “autophagic vacuole”
  17. formed from ribosome-free RER regions which fuse with pre-existing prim lyso
  18. used to remove damaged organelles…especially in nutrient deficient atrophy situations
  19. lyso also used to store things that cant be metab
  20. lyso deficiency is bad genetic disease
  21. Mito Alterations – change in #/size of mito
  22. Megamitochondria = huge mito seen in alc liver
  23. Cells w/ many or larger mito have a “eosinophilic” (aka pink) appearance
  24. SER Induction – SER hypertrophy
  25. Barbiturate abuse
  26. Increased SER volume leads to more efficient metab of drugs (tolerance)

Intracellular Accumulations

  1. Accum Processes
  2. Metab rate unable of removing normal endo substance – fat change in liver due to TAG accum
  3. Endo substance cant be metab or its deposited in amorphous/filamentous form – storage disease
  4. Abnormal exo substance accum – carbon particles
  5. Lipids – abnormal accum of TAG in parenchymal cells
  6. Steatosis = fatty change caused by prot malnut, diabetes, obesity, anoxia and alcohol abuse
  7. Foam cells – macrophages filled w/ lipids
  8. Atherosclerosis – fat under inner layer of artery (usually cholesterol)
  9. Xanthomas – intracellular accum of chol in macrophages
  10. Formed by Clusters of foamy cells in subepithelial con tis
  11. Cholesterolosis – accum of chol filled macros in gallbladder
  12. Proteins – less common than accum of lipids
  13. Russel bodies – eosiniphilic inclusions formed by enlarged ER of plasma cells synthesizing immunoglobulins
  14. Alpha-1-antitrypsin – deficiency causes accum of trypsin in liver ER
  15. Glycogen - seen in people w/ glucose/glycogen metabolism problems (diabetes)
  16. Pigments – endo or exo colored things that accumulate
  17. Carbon – most common exo
  18. Inhaled and picked up by alveolar macros then taken to tracheobronchial lymph nodes
  19. Anthracosis = blackening of lungs
  20. Lipofuscin – wear and tear/aging pigment
  21. Derived from lipid peroxidation of polyunsat lipids of membranes
  22. Not injurious itself, but indicative of free radical injury
  23. Prominent in aging livers and hearts, malnourishment, and cancer cachexia
  24. Accompanied by organ shrinkage (brown atrophy)
  25. Iron : Hemosiderin – hemoglobin deprived, gold/brown pigment where iron is stored
  26. Accumulates due to excess iron
  27. Normally iron is carried by TRANSFERRINS and stored in association with APOFERRITIN to form FERRATIN MICELLES
  28. excess causes ferritin to form hemosiderin
  29. Hemosiderosis – common bruise
  30. hemoglobin transformed to hemosiderin
  31. green color caused by biliverdin
  32. yellow caused by bilirubin
  33. Hemochromatosis – liver/pancreas damage
  34. leads to liver fibrosis, heart failure, diabetes
  35. Bilirubin – normal bile pigment; accum called jaundice
  36. Calcium – abnormal deposition of Ca salts
  37. Dystrophic – occurs in dying tis
  38. Sign of previous injury OR cause of dysfunction
  39. calcific valvular disease
  40. atherosclerosis
  41. Metastatic calcification – occurs in normal tissue when there is hypercalcemia > 11mg/dL
  42. When in lung can cause respiratory deficits
  43. Nephrocalcinosis – Ca deposits in kidneys
  44. leads to renal damage