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61 Cards in this Set
- Front
- Back
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what's the diff in necrosis vs apoptosis?
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Necrosis- groups of cells are killed by injurious agents
Apoptosis- individual cells are induced to commit suicide |
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what specific actions happen in apoptosis and necrosis?
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apoptosis:
ATP-dependent Cell membrane intact Organelles intact No inflammation necrosis: ATP not required Cell membrane rupture Organelles rupture Inflammation |
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what's the morphology of apoptosis?
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Cell shrinkage
Chromatic condensation Plasma membrane wrinkles/blebs Fragmentation into apoptotic bodies Phagocytosis of apoptotic cells/bodies |
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what do apoptotic cells look like in H & E sections?
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Oval mass of intensely eosinophilic cytoplasm with dense chromatin fragments; occurs rapidly; no inflammation
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what viral infections have pathologic apoptosis?
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HPV- E6 protein inactivates p53 --> cancer
EBV- makes Bcl-2-like substance --> prevents cells from dying HIV- infected cells make high levels of FasL which induce apoptosis in HIV-uninfected CD4 cells |
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what are some exs of physiological/good apoptosis?
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*Embryology- fingers and toes/maleness
*Hormone-dependent- endometrial cells shed on estrogen withdrawel; breast duct regression after weaning *Neutrophils (PMNs) disappear in acute inflammation *Cytotoxic T cells eliminate virus-infected cells |
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what are some exs of pathologic apoptosis?
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Radiation and anticancer drugs damage DNA and apoptosis follows (role of p53)
Hypoxia- apoptosis (if mild) or necrosis if the hypoxia is severe Decreased cell death in lymphomas (Bcl-2) Misfolded proteins |
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what are some of the biochemical events in apoptosis?
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*Caspases (cysteine proteases) cleave the cytoskeleton and activate DNAses
*DNA breaks into 50- to 300-kilobase pieces; further broken into multiples of 200 base pairs by endonucleases (Ca++ and Mg++)- demonstrated as a “ladder pattern” on agarose gel; also proteases. *Phosphatidylserine (steak sauce) is exposed and attracts macrophages with little “collateral damage” |
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what are the main mech of apoptosis in cells?
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intrinsic/mitochondria pathway:
cell injury- growth factor withdrawal, DNA damage (by radiation, toxins, free radicals), protein misfolding (ER stress) extrinsinc/death receptor pathway: receptor ligand interactions- Fas TNF receptor 1 |
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what's the major mech of apoptosis in cells? describe.
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intrinsic pathway:
Increased mitochondrial permeability and release of pro-apoptotic molecules (cytochrome c) Pro: 1. membrane- Bim, Bid, Bad and Bax, Bak 2. cytoplasm- Smac/DIABLO Anti: Bcl-2, Bcl-x |
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what are exs of diseases where TNF is involved?
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Crohn's
rheumatoid arthritis |
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if lymphoma that makes lots of Bcl-2, how can you fight the disease?
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block the Bcl-2!
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what do caspases do?
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cleave cytoskeletal and nuclear matrix proteins and result in DNA cleavage into fragments giving “DNA Ladder pattern” by agarose gel electrophoresis.
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how do you remove apoptotic bodies?
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Apoptotic cells are coated by Phosphatidyl serine (which “flips out”) or C1q leading to early recognition and removal by macrophages. Thrombospondin is an adhesive glycoprotein.
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what happens if Radiation or chemotherapy damages DNA?
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p53 accumulates
Cell cycle arrested at G1 (allows repair) If repair fails, p53 triggers apoptosis |
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what happens if p53 is lost or mutated?
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cancer!
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what's the role of Fas (CD25)? if mutated?
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FasL induces apoptosis in lymphocytes that recognize “self”; Fas/FasL mutations may cause autoimmune disease
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what does TNF/TNFR1-TRADD-FADD cause?
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caspase activation and APOPTOSIS; TNF activates NF-kB which aids cell SURVIVAL and is antiapoptotic
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what's the role of Foreign Ag-CTLs- ?
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lymphocytes produce PERFORMIN which allows entry of GRANZYME which activates caspases; CTLs kill target cells
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what if you have too little or too much apoptosis?
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“Too little”:activity diminished in certain cancers
“Too much”:neurodegenerative diseases, ischemic injury, virus-induced lymphocyte depletion |
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what are diseases influenced by defective apoptosis? what's the effect?
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*50% of human cancers have p53 mutations
*Hormone-dependent tumors (breast, prostate) *Follicular lymphomas and colon cancers express high levels of Bcl-2 (translocation of bcl-2 gene) *HPV- protein E6 binds and inactivates p53 *EBV- proteins that mimic or increase production of Bbcl-2 *Autoimmune disorders |
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what's the diff b/w Hashimoto's thyroiditis and Graves' disease?
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Hashimoto's: hypothyroidism
thyroid producing cells are destroyed if T cells have FasL ligand and interact w/ thyroid cells, cause destruction Graves': hyperthyroidism T cells that destroy thyroid cells are destroyed if ligand on thyroid cells, knockout the T cells, and allow thyroid cells to keep being made |
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what are some conditions w/ increased apoptosis?
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Neurodegenerative diseases
Ischemic injury Death of virus-infected cells (hepatitis) AIDS (death of uninfected CD4 cells) FasL+ tumors are MORE aggressive Microorganisms induce apoptosis |
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what's so bad about Pneumocystis? how so?
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*causes pneumonia in AIDS
Human macrophages are killed before they can engulf the organisms Apoptosis is triggered in macrophages by polyamines |
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when does apoptosis become pathologic?
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when it's increased or decreased
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what may be the key for new chemotherapeutic and antimicrobial agents?
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apoptosis!
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how does Velcade (bortezomid) work?
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- blocks proteasomes in multiple myeloma; proteins accumulate which are toxic to myeloma cells
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how does Genasense (oblimersen) work?
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- blocks production of BCL-2 in lymphomas rendering them more susceptible to other anticancer drugs
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what are some subcellular responses to injury?
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Primary lysosome- hydrolytic enzymes
Lysosome/vacuole fusion- secondary lysosome or phagolysosome Heterophagy: takes things from outside cell and eats it Autophagy: eats things in cell Others- lipids, proteins, filaments, Ca++ |
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how big are cytoskeletal objects normally?
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Microtubules- 25 nm
Actin filaments (thin)- 8 nm Myosin filaments (thick)- 15 nm Intermediate- 10 nm |
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what are illnesses resulting from abnormal microtubules?
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*Sperm motility deficiency “YBCS syndrome”
*Immotile cilia syndrome (Kartagener’s Syndrome) |
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what are some meds that result in abnormal microtubules?
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Colchicine- disrupt microtubule formation and inhibit PMN migration; gout therapy
Vinca alkaloids- antitumor; disrupt the mitotic spindle |
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what are illnesses that result from abnormal intermediate filaments?
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Mallory bodies (alcoholic hyalin)- keratin IM
Neurofibrillary tangles- neurofilament IM seen in Alzheimer’s Disease |
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why does the body get intracellular accumulations?
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1. Normal substance that cannot be metabolized- fatty liver (triglyceride)
2. Genetic defect in metabolism of a substance (alpha-1-antitrypsin deficiency and “storage diseases” like Gaucher’s) 3. No normal enzymes to degrade an abnormal substance (silica-silicosis) |
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when do you see fatty change (steatosis)?
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Triglycerides accumulates in parenchymal cells
Alcoholism, protein malnutrition, anoxia |
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what stain shows fat cells?
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Oil Red O stain
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what's the problem in Gaucher's disease?
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body doesn't have cerebrosidase, so cerebroside accumulates in the liver and spleen
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what's the prob in Tay Sachs disease?
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deficiency in hexosaminidase, so probs in CNS
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what's silica? can get?
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sand particles in lung.. can get silicosis
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what's prob in Atherosclerosis?
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too much HDL in blood
get deposited in intima of blood vessels and w/i macrophages there's an inflamatory and fibrotic response and get bad aortas *smooth muscle cells and macrophages (foam cells) |
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what's the effect of protein accumulation on kidney? how does it look?
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Renal failure- reabsorption of filtered protein in the proximal tubule accelerates
Vesicles of protein fuse with lysosomes and appear as pink hyalin droplets in the tubules |
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when do you have protein accum?
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if have protein that won't work w/ chaperone system (repair) and won't be taken up into ubiquitin, can't be removed
ex: amyloid- body can't remove it |
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what are protein folding errors? (messed up chaperones)
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Alpha-1-antitrypsin deficiency
Cystic fibrosis Familial hypercholesterolemia Unfolded Protein Response- caspase-12 is activated with apoptosis induction; Alzheimer’s, Huntington’s, Parkinson’s Amyloidosis- amyloid not eliminated |
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what's hyaline change?
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Homogenous, glassy, pink appearance
Eg. Mallory alcoholic hyalin |
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what stain shows iron?
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Prussian blue stain
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what are some imp pigments?
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*Carbon (exogenous)
*Lipofuscin- lipid and phospholipid polymers complexed with protein; wear-and-tear pigment- liver and heart of aging patients *Melanin- dihydroxyphenylalanine (from Tyr): melanoma and benign neva *Hemosiderin- iron-ferritin forms hemosiderin granules; hemosiderosis (in macrophages); hemochromatosis (in parenchymal cells) |
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is lipofuscin pathologic?
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no- just deposited in cells as they age
see in myocytes |
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what are some exs of parenchymal cells?
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liver- hepatocytes
kidney- glomeruli pancreas- amylase making cells and insulin making cells |
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describe dystrophic calcification:
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necrotic tissue; serum Ca++ normal; atheromas, heart valves; psammoma body-meningomas and adenocarcinomas /asbestos body- feruginous bodies
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describe metatstatic calcification:
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hypercalcemia; parathyroid, skeletal metastases, vitamin D, renal failure; lungs, arteries
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what are feruginous bodies coated in?
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Ca and Fe
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is metastatic calcification pathologic?
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no- caused by pathologic condition
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cells don't live long in which diseases?
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Werner's - don't have lots of telomerase
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what's telomerase high in?
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germ cells and stem cells
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what stain shows cysts of Pneumocystis?
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silver stain
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what's main diff b/w apoptosis and necrosis?
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apoptosis- cleaved at specific places and theoretically can be reused by cell
necrosis- everything smashed to bits |
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what are the 1st caspases turned on?
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8, 9, 10
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what are execution caspases?
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caspases lower than 8, 9, 10
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are caspases turned on in intrinsic and extrinsic pathway?
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caspases are turned on and 10-11 caspases are active --> turn on other enzymes to digest cells: orderly
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what lets cytochrome c escape?
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antagonism of Bcl-2
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how do neutrophils die?
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apoptosis- only live a few hrs
*don't get very eosinophilic |
