Section 1
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Coagulative Necrosis - cause and histological findings
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Date created
Mar 14, 2020
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Section 1
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Coagulative Necrosis - cause and histological findings
- Ischemia - Enzymes are denatures and proteolysis is blocked, thus the tissue retains its structure histologically. Tissue is firm. - pink cytoplasm but nuclei disappear
TLR mediation of acute inflammation - macrophage CD# for LPS
- TLRs on innate cells; bind PAMPS - CD14 on macrophages (TLR4) recognizes LPS of gram negative bugs - NF-kB activation
Fat necrosis - 2 types - pathophys of the one - histology
Enzymatic or traumatic - enzymatic: pancreatic lipases break down TAGs and liberated FAs bind calcium --> saponification - saponified fat appears blue on H&E
Complement Pathways (3) - the end result of all three
- Classic: C1 binds IgM or IgG that is bound to Ag (GM makes classic cars) - Alternative: microbial products directly activate complement - Mannose-binding lectin pathway All activate c3 covertase= C3a and C3b C3b activates c5 convertase= c5a and c5b C5b complexes with c6-c9 to form MAC
Primary mediator of hepatic acute phase reactant production 5 upregulated reactants 2 downregulated What is the logic for each?
- IL-6 - More (upregulated) FFiSH in the C: Ferritin: iron storage from microbes Fibrinogen: clotting Serym Amyloid A: amyloidosis Hepcidin: prevents iron abs from gut C-Reactive Protein: fixes complement and facilitates phagocytosis Downregulated: Albumin: conserve AA for positive reactants Transferrin: iron sequestraino
Where does leukocyte extravasation occur?
postcapillary venules
Macrophage response to acute inflammation - time to arrive - mechanism of ingestion Outcomes (molecular mediators) - Res - Continued acute - Abscess - Chronic
- after 2-3 days - ingest organisms and debris with enzymes (O2 independent) Resolution: release IL-10 and TGF B to decrease immune response Continued acute: IL-8 to recruit more neutrophils Abscess: macs mediate the formation of fibrous tissue around the acute inflammatino Chronic: macs presents antigen to CD4
Mechanism of the anaphylatoxins (c3a and c5a)
Trigger mast cell degranulation and thus histamine-mediated vasodilation and increased vascular permeability
Irreversible cell injury - 4 findings/processes
- plasma membrane breaks down and enzymes leak into the serum (troponin) - Ca+2 influx (typically low in the cytosol) activates degradation enzymes - Lysosomal rupture and autolysis - Nuclear degradation (pyknosis, karryhexis, karyolysis)
Pyknosis Karyorrhexis Karyolysis
- nuclear condensation - fragmentation due to endonuclease-mediated cleavage - dissolution
3 mechanisms of mast cell activation in acute inflammation Immediate and delayed response
1. IgE cross-linking 2. trauma 3. C3a and C5a Immediate: histamine release for arteriole vasodilatation Delayed: AA metabolites, leukotrienes
5 stimuli for chronic infection
1. Persistent acute infection 2. Infection with intracellulars (TB, fungi, viruses, parasites) 3. Autoimmune 4. Some cancers 5. Foreign materials
4 mediators of vasodilation (the level of the arteriole) in inflammation
- histamine - prostaglandins - NO - bradykinin
Role of Hageman Factor in acute inflammation - activation? - three pathways is then initiates
Activated upon exposure to subendothelial or tissue collagen. It then activates: 1. Coag and fibrinolytic systems 2. Complement 3. Kinin system: Kinin cleaves HMWK to bradykinin
Mechanism of fever upon pyrogen exposure
Pyrogens (like LPS) induce macrophage expression of IL-1 and TNF These increase COX activity in the hypothalamus and PGE2 is generated --> increased temperature set point
gangernous necrosis (2 types)
Dry or wet (liquefactive necrosis due to superimposed infection)
3 mediators of pain in inflammation
- bradykinin - PGE2 - histamine
Three mechanisms of ischemia
- decreased arterial perfusion - decreased venous drainage (Budd-Chiara, Testicular torsion) - Shock
Test for chronic granulmatous disease MPO deficiency (increased infection risk?)
Nitroblue tetrazolium test: turns blue in presence of O2- - Can't make bleach; normal NBT test; increased risk for Candida infection but otherwise asx
3 step process of the oxidative burst
1. O2 to O2- via NADPH oxidase 2. SOD converts to H2O2 3. MPO to bleach
Extrinsic Apoptosis Pathway
- FasL binds to Fas (CD95) - TNF-Alpha binds to its receptor - CH8+ cell mediated perforins and granzymes All three activate caspases.
Liquefactive Necrosis
- abscesses and brain infarcts - Neutrophils/Migroglia release lysosomal enzymes which degrade the tissue - histology: neutrophils and cell debris
CD4 cell activation - first interaction - two possible outcomes and the relevant cytokines
MHCII presentation of Ag by APC - B7 (CD80/86) on APC binds CD28 on CD4 (28/4=7) 1. Th1 subset secretes INF-gamma: activates macs, promotes IgM to IgG switch, and promotes Th1 while inhibiting Th2) 2. Th2 secretes IL-4 (facilitates IgE), IL-5 (eosinophils and IgA switch), and IL-13
Chediak-Higashi syndrome - inheritance - pathophys - findings (6)
AR - issue with phagolysosome formation; defective microtubule function - findings: increased pyogenic infections, neutropenia, giant granules in leukocytes, defective primary hemostasis (platelets are affected), albinism, peripheral neuropathy in the long nerves
Severe Combined Immunodeficiency (SCID) 3 etiologies Rx
Defective cell-mediated and humoral immunity 1. Cytokine receptor defects 2. ADA deficiency: inability to break down AMP properly; buildup of waste is toxic to the lymphocyte 3. MHC II deficiency Susceptible to all infections and requires sterile isolation until stem cell tx.
Three antioxidants
Vitamins A, C, E
5 mediators of swelling (post-capillary venule leak) in inflammation
- LTC4, D4, E4 - Histamine - Serotonin
Localized Amyloidosis (protein deposit and the location/description) - Alzheimers - T2DM - Medullary thyroid cancer - Isolated atrial amyloidosis - Systemic senile
- beta-amyloid from APP - islet amyloid polypeptide from amylin deposits - Calcitonin - ANP; normal aging - Transerythrin; in the ventricles
Fenton reaction
Fe+2 generates hydroxyl radicals
Intrinsic Apoptosis Pathway - 3 examples of how this is initiated - key proteins involved in the process (4)
- embryogenesis, removal of regulation factor (like IL-2 after an immune reaction), exposure to injurious stimulus - BCL-2 stabilizing the mitochondrial membrane, preventing Cytochrome C leakage (Follicular lymphoma t14:18) - BAX and BAK form pores in the membrane, allowing Cytochome C to leak which activates caspases
CD8 cell activation
Signal 1: bindings of foreign peptide on MHC 1 Signal 2: IL-2 from Th1 cell activates for killing
Hereditary Amyloidosis (2) - cause and the characteristics of the cardiomyopathy
- Mutated transerythrin - Familial amyloid cardiomyopathy: deposits in the ventricular endomyocardium causing a restrictive myopathy - Familial Amyloid Polyneuropathy
Two types of infarcts
Red infarct: occurs in venous occlusion and in tissues with multiple blood supplies (liver, lung, intestines, testes) and with reperfusion (free radicals) Red is Reperfusion Pale infarct: in solid organs with only one blood supply (heart, kidney)
Caseous Necrosis - three causal infections
- Organisms that form caseating granulomas: TB, Histoplasma, Nocardia - Macs form the walls
Leukocyte Adhesion Deficiency - inheritance - deficiency? With # - 3 findings
- AR - deficient integrins (CD18) - findings: delayed umbilical separation, leukocytosis (decreased tissue marginated pool), and recurrent bacterial infections that lack pus formation.
Systemic Amyloidosis (3 types) and the 5 general manifestations
1. Primary (AL): from immunoglobulin light chains 2. Secondary (AA): derived from Serum Amyloid Associated protein; chronic inflammation (RA, IBD, familial mediterranean fever) 3. Dialysis-related amyloidosis: B2-Microglobulin; ESRD Manifestations: Cardiac (restrictive myopathy), GI, Renal (nephrotic syndrome), hematologic, neurologic, MSK
CCL4 free radical injury - setting - pathophys - histological findings
Dry cleaning industry Converted to CCL3 free radical by CP450; injures the RER and impairs protein synthesis Apolipoproteins affected and fatty liver results
Three enzymes that deal with free radicals; carrier proteins?
1. SOD: O2- to H2O 2. Catalase: H2O2 to H2O and O2 3. Glutathione Reductase Transferrin and Ceruloplasmin deal with iron and copper, respectively to prevent damage. Wilson and Hemachroma are diseases that cause free radical injury.
Apoptosis - energy - activated enzymes - findings on histology (3) - degradation? - membrane and inflammation?
- ATP-mediated - Caspases -> activate proteases (break down the cytoskeleton) and endonucleases (DNA) - eosinophilic cytoplasm, basophilic nucleus, pyknosis, karyorrhexis - apoptotic bodies bleb off and are eaten by macrophages - cell membrane intact without inflammation
dystrophic vs metastatic calcification
dystrophic is a hallmark of preceding cell injury and necrosis (as in aged/damaged cardiac valves and atherosclerotic plaques) in setting of normal calcium levels; deeply blue on histology vs deposition in normal tissues in the setting of high serum calcium or phosphate levels
5 mediators of acute inflammation
1. TLRs 2. Arachadonic acid metabolites 3. Complement 4. Mast Cells. 5. Hageman factor (XII)
Familial Mediterranean Fever - genetics - pathophys - presentation
Autosomal recessive dysfunction of neutrophils that presents with fever and acute serosal inflammation. The inc SAA will deposit as AA amyloid. Presentations with symptoms similar to appendicitis, arthritis or myocardial infarction bc involves serosal surfaces of those organs
Inducers of e-selectin P-selectin
IL1 and TNF Histamine
Lipofuscin - what is it? - how is it formed?
Yellow-brown wear and tear pigment associated with normal aging. Formed by oxidation and polymerization of autophagocytosed organellar membranes. Will find deposts in the heart, colon, liver, kidney, etc of elderly person at autopsy.
Reversible cell injury - mechanism - 4 findings
Depletion of ATP leading to decreased pump activity and hypertonic cell. Cellular swelling. 1. Ribosomal detachment 2. Plasma membrane blebbing 3. Nuclear changes (chromatin clumping) 4. Loss of function
Fibrinoid Necrosis
Necrotic damage to blood vessel wall; can be immune-mediated (PAN) or due to HTN - leakage of proteins into the vessel wall (immune complex due to type three hypersensitivity or fibrin due to damaged vessel wall) - Thick and pink vessel walls
Results of chronic vs acute ischemia on cells
Atrophy vs injury
Necrosis (vs apoptosis)
Large groups of cells die due to some external insult followed by acute inflammation. Never physiologic.
Inflammasome - definition - 4 activators - result of triggering
"Multi-protein cytoplasmic complex" - Recognizes products of Dead cells Uric acid extracell. ATP crystals -Triggering results in activation of Caspase-1 which cleaves precursor forms of inflammatory cytokine interleukin 1B(IL-1B)
B-Cell activation 1. T-cell independent 2. T-cell mediated (3 steps)
1. direct ag binding to surface IgM or IgD (mature to plasma cells but a weaker response) 2. Present peptide fragment via MHCII to CD4; CD40 receptor on B binds to CD40 L on CD4; Th cell secretes cytokines to mediate class switching
Section 2
(49 cards)