Ls CELLULAR PATHOLOGY NECROSIS & APOPTOSIS osms.it/necrosis-and-apoptosis + Two main ways by which cells die NECROSIS * Cell death by injuryidisease + External triggers (eg, infection, temperature} + Internal triggers (e.g ischemia} Coagulative necrosis, * Occurs in hypoxic tissue + Structural proteins bend out of shape + Lysosomal proteins become ineffective at removing affected proteins + Cell dies, some structure remains Gangrenous necrosis + Also occurs in hypoxic tissue * Dry gangrene: tissue dries up + Wet gangrene: infection, iquetactive necrosis also occurs Liquefactive necrosis * Hydroiytic enzymes digest dead cells into ‘creamy substance Caseous necrosis + Occurs in fungalmycobacterial infections + Cell disintegrate {not fully] ~» cottage cheese consistency Fat necrosis + Occurs in response to fatty organ trauma + Adipose cell memiranes ruptured + Fatty acids combine with calcium, causing dystrophic caleifcations + Can occur in pancreas as result of inflammation (AKA pancreatitis) Fibrinoid necrosis * Occurs in malignant hypertensionfvascults + Fibrirvinflammation darvages blood vessel walls Also includes oncosis + Toxinsfischemia damage mitochondria + ATP can no longer be synthesized {e., Tonic pumps} + Sodium, water flow into cell + swelling + Cell bursts, triggers infiammmatory process APOPTOSIS + Programmed cell death + Based on caspase cascade + Pro-caspases cleaved into caspases, activating caspase 3 + Caspase 3 causes activation of cascade of caspase proteins + Cleaves various integral proteins degrading cellular components fe. nucleus, organelles, cytoskeleton) * Cel loses structure, resulting in blebs, which break off, undergo phagocytosis Intrinsic/mitochondrial pathway + Induced by stress (eg. radiation) + Process + Intracellular proteins BAX, BAK pierce rmitochonstial membrane + This allows SMACS, cytochrome C to flow out of mitochondria = SMACS binds to proteins that otherwise inhibit apoptosis * Cytochrome C binds to ATP, APAF-1, forming apoptosome + Pro-caspase 9 cleaves into easpase 9, activating caspase 3 NOTES OSMOSISORG 181CYTOSOL, BAX ae MITOCHONDRIA ° ° 2 °° GyTocHRoMe C O smacs O 20 ~ blade te Apaf-t binds toate ~ binds to PROTEINS that Inhibit APOPTOSIS oN @ | eee APOPTOSOME casense 4 CASPASE 3 OTHER CASPASES 4 APOPTOSIS macrobaage SS) Figure 244 The intrinsichnitochonatial apoptosis pathway, (Os MOSIS. Org 182 OSMOSISORGChapter 24 Cellular Physiology: Cellular Pathology Extrinsic/death receptor pathway cell AKA death domain) + Process: * Death domain changes shape, binds = External cell ritiates apoptosis by various proteins to form intemal releasing various signaling proteins signalling complex Signaling proteins bind to death + Pro-caspase & cleaves into caspase 8, receptors on cell membrane activating caspase 3 + Cytosolic end of protein dives deep into EXAMPLE 1 EXAMPLE 2. MACROPHAGE : eyToTOXIc T CELL DEATH RECEPTORS . TUMOR NECROSIS | FAS RECEPTOR: FACTOR RECEPTOR 1 (-FAS LIGAND DEATH DOMAIN oe Ecce el SIGNALING COMPLEX =— } eee (0180) , 4 ndycasense-8 vy CASPASE-8 —+> CASPASE-3 Gotuers (casease CASCADE Garorrosis Figure 24.2 Two examples of the extrinsiaideath receptor pathway. In example 1, a macrophage recognizes an old cell, a pathogenic cell, or a cell that has completed its task It releases TNF-a, which binds to the death receptor tumor necrosis factor receptor 1. in example 2, when a cytotoxic T cell detects that a cel is expressing foreign antigens, the T cell exoresses FAS ligand fn its membrane. FAS ligand binds to the death receptor called FAS receptor. In bothycases, the death domain binds ather proteins to form DISC and the caspase cascade leads to apoptosis: |) OSMOSISORG 183ONCOGENES & TUMOR SUPPRESSOR GENES * Cade for proteins involved in progression of coll cycle * Positive regulation: oncogenes stimulate cell growth, division = Negative regulation: tunor suppressor genes stop cell cycle progression, promote apoptosis, Proto-oncogenes * Code for growth factors, growth factor receptors feg. receptor tyrosine kinase) + Signal transcuction oroteins (eg. RAS GTPase}, transcrition factors (eg. MYC) apoptosis inhibitors (eg. BCL-2) + Active when cell needs to grow, divide + Translocations, amplifications, point ‘mutations turn proto-oncogenes into oncogenes » Overexpression » Eg. in Burkitt iymphoma, MYC moved from chromosome 8 to near IgH promoter on chromosome 14 = overexpression of cyclins, eyclin- dependent kinases Eg. in chronic myeloid leukemia with Philadelphia chromosome ‘Tumor suppressor genes * Cade for various tumor suppressors, other protein inhibitors + Active throughout cel cycle + Various mutations cause uncantroled cell growth, division 184 OSMOSISORG Tee BURKITT LYMPHOMA Figure 24.3 Surkit lymphoma can occur {due to translocation between portions fof chromosomes 8 and 14, resulting in ‘overexpression of proto-oncogene MYC. PHILADELPHIA CHROMOSOME PAILADEL FW eee H,0, Superoxide Hydrogen ‘rion perovide a DEFENSE AGAINST FREE RADICALS Antioxidants Eq. vitamins A, C, E + Eliminate free radicals by donating electrons Metal carrier proteins + Eg. transferrin fr iron, ceruloplasmin for copper + Bind, carry metals to prevent free radical production Enzymes + Eliminate various free radical species * Superoxide dismutase + superoxide + Catalase —+ hydrogen peroxide + Glutathione peroxidase + hydroxy! radical us on Ss H,0 Hydrol 4, radical <= Radiation Figure 247 Oxygenis an example of a molecule that can become a free radical OSMOSIS.ORG 187188 OSMOSISORG ISCHEMIA + Reduction in blood flow to organitissue —> ‘oxygen shortage Caused by blackagelcompression of blood vessel Arterial ischemia * arterial blood flow —» | oxygen received + Eg, atherosclerosis: plaque blocks arteries to heart — ischemic heart disease Venous ischemia | venous blood flow —» | drainage — | blood flow —» | oxygen received + Eg, Budd-Chiari syndrome: clot blocks hepatic vein —» liver ischemia + edemal hepatomegaly Outcomes + Sometimes, congestion —> 17 pressure + fluid forced outledema + |Loxygen — cell death (eg. tissue necrosis, infarction) + Ischemic penumbra: ischemic but still Viable tissue + Collateralization: growth of collateral vessels to serve ischemic tissue + Time to reperfusion: time taken to re establish perfusion before cells die Short + cells survive + reversible Long + cel’s die ireversible INFLAMMATION + Immune response described by four key signs: * Calor: heat * Dolor: pain + Rubor: redness Tumor: swelling + May also involve “Tunetio laesa" (AKA loss of function) + Tiggered by external, internal factors + External * Non-microbial: allergens, iritants, toxic compounds, * Microbial: virulence factors, pathogen associated molecular patterns {PAMPs} + Internal Damage associated molecular patterns (DAMPs) Example process + PAMPs, DAMPs recognized by pattern recognition receptors (PRRs} on immune calls + Activate cells, sparking inflammatory response + Mast cells contain granules with inflammatory mediators “Eg. histamine, serotonin, cytokines, and eicosanoids + — separate endothelial cells on nearby capillaries + Macrophages eat any invading pathogens + Cytokines cause capillaries to enlarge, t vascular permeability + Endothelial cells release nitric oxide for vasodilation, 1 vascular permeability * Leukocytes, especially neutrophils, attracted through capilaries by chemokines, microbial products; squeeze through membrane AKA extravasation + Leukocyte follows gradient of inflammatory mediatorsChapter 24 Cellular Physiology: Cellular Pathology + Neutrophils phagocytose pathogens + Dendritic cells phagocytose pathogens, immediately before destroying themselves present antigens to T lymphocytes, + Antioodies bound to pathegens activate ‘activating adaptive immune system ‘complement system + Ends with tissue repair + Aids in opsonization, kills pathogens by lysis Figure 24.8 1: DAMPs and PAMPs activate immune cells. 2: Macrophages phagocytose pathogens at the site of inflammation. Mast cells release inflammatory mediators that widen the distance between adjacent endothelial cells, 3: Endothelial cells release nitric oxide» vasodilation, vascular permeability. ‘COMPLEMENT SYSTEM u ' ATTRACT LEUKOCYTES “+ HELP w/OPSOMRZATION Figure 24.9 1: Neutrophils are the first leukocytes recruited during the acute inflammatory process, They squeeze through the gap between endothelial cells extravasation} and follow the gradient of inflammatory mediators to the site of inlarnmation. 2: Neutrophils quickly pphagocytose pathogens. While this is happening, complement proteins are actvated by the presence of pathogens and help with opsonization {they bind to microbes so leukocytes can ‘more easly eat them). Some can also kil pathogens by forming a channel in their membranes, (OsMosis.org OSMOSIS.ORG 189