Path Cell Injury III (3)

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Path Cell Injury III (3)
2014-01-24 22:19:30
MBS Pathology
Exam 1
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  1. What are the 2 pathways through which cell death can proceed?
    • 1. Necrosis: always pathologic
    • 2. Apoptosis: can be physiologic or pathologic
  2. Necrosis ("accidental cell death")
    • a spectrum of morphologic changes that follow cell death in living tissue, largely resulting from the progressive degradative action of enzymes on a lethally injured cell
    • characterized by 2 processes: enzymatic digestion & denaturation of proteins
    • is an irreversible loss of homeostasis
  3. Morphological Changes of Necrosis
    • increased eosinophilia (high eosinophil count)
    • blebbing of the cell membrane
    • cell & organelle swelling
    • *nuclei changes (the only unequivocal evidence that a cell is dead)
    • chromatin clumping
    • ↑ plasma membrane permeability
    • membrane damage
    • ATP depletion
    • general inflammation
  4. Necrotic
    • term for a tissue when necrosis happens to a large number of cells
    • dead cells release nuclear & cytoplasmic components into the environment which trigger an influx of inflammatory cells
  5. What differentiates necrosis from apoptosis?
    • the presence of immigrant inflammatory/immune cells
    • they are only present during necrosis
    • inflammatory cell migration DOES NOT occur during apoptosis
  6. Types of Necrosis
    • 1. Coagulative (most common)
    • 2. Caseous
    • 3. Liquefactive
    • 4. Fat
    • 5. Fibrinoid
    • 6. Gangrenous
  7. What is the most common form of necrosis?
    • Coagulative Necrosis
    • the basic outline of the dead cell is preserved for a few days
    • lysosomal hydrolytic enzymes incompletely degrade cell contents
    • nuclear changes indicative of necrosis are present (pyknosis/karyorrhexis/karyolysis)
    • necrotic cells are eventually removed via phagocytosis done by infiltrating inflammatory cells (neutrophils & macrophages)
  8. What is a clinical example of coagulative necrosis?
    • myocardial infarct (MI)
    • an infarct = a localized area of coagulative necrosis
    • ischemia due to a blood vessel obstruction (eg. thrombus) can lead to coagulative necrosis in affected tissue in all organs EXCEPT the brain
  9. Caseous Necrosis
    • often encountered at the site of a Tuberculous infection
    • are white & cheese-like areas in the necrotic tissue
    • under the microscope necrotic area appears as amorphous granular debris enclosed within a distinctive border → characteristic appearance of a granuloma
  10. Granuloma
    • when macrophages - in certain cases of chronic inflammation - collect in layers surrounding infectious material (silica, TB, asbestos, etc) & fuse, forming giant cells
    • structure = layers of macrophages surrounding a central core
  11. Liquefactive Necrosis
    • a complete digestion of dead cells & tissue is turned into a liquid viscous mass
    • there is a pus fluid product of this process made up of leukocytes & dead cell/tissue debris liquefied by proteolytic enzymes of inflammatory cells
    • seen in some focal bacterial or occasional fungal infections
  12. What is a clinical example of liquefactive necrosis?
    • hypoxic death (brain infarct) results in liquefactive necrosis
    • result of stroke
    • also any pus formation = liquefactive necrosis
  13. Fat Necrosis
    • not a specific pattern of necrosis, but a descriptive term for focal areas of fat destruction usually caused by activated pancreatic lipases in parts of the pancreas or peritoneal cavity where it shouldn't be
    • fat cells are liquified by lipases
    • released FAs combine w/ Ca2+ to form grossly visible chalky spots (fat saponification)
    • under the microscope the tissue contains outlines of fat cells w/ basophilic Ca2+ deposits surrounded by inflammatory processes
  14. Apoptosis ("programmed cell death")
    • a coordinated, internally programmed series of events triggered by specific signals that activate specific genes
    • cells shrink, organelles remain intact, & chromatin is degraded systematically
    • membrane blebs (chunks of cell) can be phagocytosed by neighboring cells
    • there is NO inflammatory response
  15. Causes of Apoptosis
    • Embryogenesis
    • Hormone/GF dependent involution: in a dependent tissue, withdrawal of a hormone leads to apoptosis in the tissue (eg. breast after menopause, or immune cells at the end of an immune response)
    • Cell Proliferation: cell loss by apoptosis helps to maintain a constant number (homeostasis) of cells (eg. germinal centers lymphoid tissues)
    • Tumors
    • Immune/Inflammatory Responses (can CAUSE)
    • Atrophy
    • Viral diseases (eg. HIV)
    • Injurious stimuli
  16. Morphology of Apoptosis
    • Cell shrinkage
    • Chromatin condensation
    • Cytoplasmic blebs & apoptotic bodies
    • Phagocytosis of apoptotic cells & bodies
    • Little → No inflammation
  17. What is THE most characteristic feature of apoptosis?
    • chromatin condensation
    • chromatin condense into dark masses (margination) under the nuclear envelope → forms a characteristic pattern
    • the nucleus itself may break up, producing 2 or more pieces
  18. Apoptotic Bodies
    • membrane-bound apoptotic bodies containing cytoplasm & tightly packed organelles; may contain nuclear fragments
    • develop from the breaking off of extensive surface blebbing
  19. Biochemical Features of Apoptosis
    • Formation of MPT (mitochondrial permeability transition pore)
    • Caspase activation (type of proteases)
    • Protein cleavage & cross-linking
    • DNA fragmentation (via endonucleases & DNA “ladder”)
    • Phagocytic Recognition
  20. DNA Laddering
    • observable DNA fragmentation in a characteristic "ladder" pattern that can be seen using gel electrophoresis
    • a distinctive feature of DNA degraded by caspase-activated DNase (CAD), a key event in apoptosis
    • CAD cleaves genomic DNA at internucleosomal linker regions, resulting in DNA fragments that are multiples of 180–185 bps in length
  21. What happens to cell surfaces during apoptosis?
    • special molecules like phosphatidylserine & thrombospondin that promote phagocytosis appear
    • the presence of special molecules on the surface allow apoptotic cells to be ‘recognized’ by macrophages or adjacent cells WITHOUT the release of pro-inflammatory compounds
  22. Phosphatidylserine
    • usually found in the inner portion of the plasma membrane
    • is found on the outer portion of the membrane (‘flipped out’) on the surface of apoptotic cells
  23. Thrombospondin
    an adhesive glycoprotein that's expressed on the surface of apoptotic cells
  24. What are the 4 separable but overlapping components of apoptosis?
    • 1. signaling pathways that initiate apoptosis
    • 2. control & integration (the 2 pathways may be interconnected in some situations, eg. the binding of Fas may activate a protein that in turn activates the intrinsic pathway)
    • 3. execution phase consisting of the actual cell death common to all initiating pathways (accomplished by caspases)
    • 4. phagocytosis of dead cells
  25. What are pathologic activators of apoptosis?
    • viral infection, heat shock, toxins, tumor suppressors, oxidants/free radicals
    • therapy induced apoptosis = UV/gamma radiation & chemotherapeutic drugs
  26. What are physiologic activators of apoptosis?
    intrinsic (mitochondrial) & extrinsic (death receptor-initiated) pathway inducers
  27. Intrinsic Pathway
    • activated by growth factor withdrawal, survival factor withdrawal, or glucocorticoids
    • upon mild ischemia, removal of nutrients, there is a withdrawal of growth factors (& the like)
    • when apoptosis signal is received, pro-apoptotic Bcl-2 proteins (eg. BAD) are DEphosphorylated
    • they bind to proteins on the outer mitochondrial membrane causing a LOSS of mitochondria membrane channel control
    • cytochrome C is released through MPTs & begins the caspase amplification
  28. Extrinsic Pathway
    • induced by TNF-α or FasL (Fas ligand) molecules binding to plasma membrane receptors [apoptosis is receptor mediated]
    • the cell that presents 1 of the 2 ligands will live & communicates to the cells with receptors they should undergo apoptosis
    • once bound the receptor's death domain is activated, initiating the caspase cascade
  29. Adapter Proteins
    can directly transmit death signals to the execution mechanisms
  30. Bcl-2
    • a family of proteins that plays a critical role in regulating apoptosis
    • Anti-apoptotic: (Bcl-2, Bcl-x, and Mcl-1) suppress apoptosis by direct action on mitochondria to prevent increase in permeability or by interactions with other proteins
    • Pro-apoptotic: (Bax, Bak)
  31. p53
    • is normally involved in preserving the viability of an injured cell when DNA damage can be repaired, but propels it toward apoptosis after irreparable harm has occurred
    • can induce apoptosis by influencing the balance of pro vs. anti-apoptotic Bcl-2 proteins
  32. Apoptosis Execution Phase
    • whatever the causative stimuli, the 2 initiating pathways converge to a cascade of caspase activation (the final phase of apoptosis)
    • intrinsic: initiator caspase-9 is activated
    • extrinsic: initiator caspase-8 & 10 are activated
    • active initiator caspases activate a number of execution caspases (caspase-3 & -6)
  33. Execution Caspases
    cleave DNA, degrade structural components of the nuclear matrix, digest cellular proteins, etc.
  34. What are some examples of cells that die by apoptosis because they are deprived of growth factors?
    • 1. hormone-sensitive tissue deprived of the relevant hormone
    • 2. lymphocytes that aren't stimulated by cytokines & antigens
    • 3. neurons deprived of nerve growth factors
    • in these examples apoptosis is triggered by the intrinsic (mitochondria) pathway
  35. How can protein misfolding lead to apoptosis & in which diseases is this phenomenon particularly relevant?
    • newly synthesized proteins fold into their proper shapes in the ER with the help of chaperones
    • misfolded polypeptides are linked w/ ubiquitin & targeted for proteolysis
    • if unfolded/misfolded proteins accumulate in the ER, the cell responds w/ ‘unfolded protein responses’
    • if these responses cannot handle all the misfolded proteins accumulating, the cell activates caspases & induces apoptosis
    • *the pathogenesis of neurodegenerative diseases (Alzheimer, Huntington, and Parkinson) involves the accumulation of misfolded proteins
  36. Cytotoxic T Lymphocyte-Mediated Apoptosis
    • foreign antigens presented on the surface of infected cells are recognized by cytotoxic T lymphocytes (CTLs)
    • upon activation CTLs secrete perforin (transmembrane pore-forming molecule), which promotes entry of the CTL granule serine proteases called granzymes into target cells
    • Granzymes activate a variety of cellular caspases
    • CTLs kill target cells by directly inducing the effector phase of apoptosis (they can also bind FasL to Fas receptors, triggering apoptosis via the extrinsic pathway)
  37. Lysosomal Storage Diseases
    • example of a normal endogenous substance accumulating because of enzyme defects (usually inherited)
    • caused by a lack of enzyme needed for metabolism of a substance
    • eg. Gaucher disease results from a deficiency in glucocerebrosidase, which results in accumulation of glucosylceramide in cells
  38. Steatosis (Fatty Change)
    • abnormal accumulation of TAGs in parenchymal cells
    • most often affects the liver, but accumulations can be found in heart, muscle, or kidney
    • excess accumulation of TAGs in the liver is caused by excessive entry OR defective metabolism/export of lipids
    • defects in uptake, catabolism, or secretion of fat in the liver can lead to accumulation
  39. Atherosclerosis
    • in atherosclerotic plaques, cholesterol & cholesterol esters are found in the cytoplasm of smooth muscle cells & macrophages in the tunica intima of the aorta & large arteries
    • some cells may rupture & release the lipids in the extracellular space
    • extracellular cholesterol esters may crystalize in the shape of long needles, producing characteristic ‘cholesterol clefts’ in tissue sections
  40. Intracellular Protein Accumulation
    • can arise from defects in their synthesis, folding, transport, or secretion
    • Russell bodies in plasma cells: protein accumulation
    • α-1-antritrypsin deficiency: secretion defects
    • Alzheimer's: cytoskeletal protein accumulation
    • amyloidosis: ABnormal protein accumulation
  41. Exogenous Pigments
    • carbon is the MOST common exogenous pigment
    • inhaled carbon particles are phagocytosed by macrophages in the lungs, then transported through lymphatic channels to lymph nodes
    • however b/c there are no enzymes capable of digesting carbon particles, the pigment stays in the lymph nodes
    • another example = tattoo ink, silicon
  42. Hemosiderin
    • hemoglobin-derived, golden yellow/brown pigment is the major storage form of iron if there is excess
    • small amounts of hemosiderin are present normally in the mononuclear phagocytes (eg. macrophages) of bone marrow, spleen, & liver (organs involved in the breakdown of RBCs)
  43. Dystrophic Calcification
    • macroscopic deposition of calcium salts in injured tissue, often a cause of organ dysfunction (eg. calcific valvular diseases & atherosclerosis)
    • deposits of calcium salts are found in nonviable or dying tissues (areas of necrosis) such as atheromas, heart valves, TB lymph nodes, in breast cancers, & in foci of enzymatic necrosis of fat
    • morphologically, the calcium salts appear macroscopically as fine white granules
    • microscopically, the salts have a basophilic, amorphous granular appearance
  44. What is one difference between dystrophic & metastatic calcification?
    • calcium metabolism in dystrophic calcification is normal
    • in metastatic calcification it's ABnormal
  45. Metastatic Calcification
    • characterized by a high serum calcium
    • the calcium is deposited in normal tissues
    • mainly found in the interstitial tissues of the gastric mucosa, lungs, systemic arteries, & pulmonary veins
    • these deposits don't cause clinical dysfunctions of the affected organs, however calcium stones in the gall bladder & kidneys can cause pain & affect organ function
  46. What can cause metastatic calcification?
    • increased secretion of parathyroid hormone in hyperthyroidism w/ subsequent bone resorption
    • destruction of bone tissue
    • vitamin D-related disorders
    • renal failure w/ secondary hyperparathyroidism & phosphate retention
  47. Hyaline Change
    • a descriptive histologic term; is not a specific marker for cell injury
    • describes an alteration within cells or in the extracellular space
    • appears homogeneous, glassy, & pink in routine H&E stains
    • can be produced from multiple mechanisms
  48. Alcoholic Hyaline
    • accumulation of keratin intermediate filaments (Mallory bodies) in hepatocytes
    • example of extracellular hyaline is seen in the hyalinized walls of arterioles in the kidney of a person suffering from long standing hypertension