Pathology Inflammation
Terms
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- inflammation sentries
- fibroblasts, endothelial cells, dendritic cells, mast cells, macrophages--release chemokines and whatnot
- chemokines
- small molecular wight peptides secreted by resident macrophages, fibroblasts, endothelial cells which attract and activate neutrophils, monocytes, and lymphocytes. i.e IL8
- site of entry for cells and plasma proteins at the site of tissue injury
- post capillary venules
- exudate
- protein rich fluid that egresses into tissue thanks tue increased permeability of post capillary venules in inflammation
- transudate
- low in protein and cells and results from increased hydrostatic pressure (heart failure) or low oncotic pressure (liver, kidney disease)
- causes of pain in inflammation
- nerve injury, locally produced cytokines like bradykinin
- Source of histamine
- mast cells, platelets
- source of bradykinin
- plasma cleavage product of high molecular with kininogen HMWK
- stasis (inflammation)
- slow flow that allows phagocytes to attach to vessel wall, results from increasing viscosity secondary to loss of plasma
- PMN description; source, lifetime, function, granule types
- 1) produced in marrow 2) viable less than 24 hours after migration to injury 3) major cell in acute inflammatory response 4) primary cell against bacteria 5) two granule types: azurophil and secondary
- contents of azurophil granules
- proteases, myeloperoxidase, lysozyme
- contents of specific (secondary) granules
- lysozyme, lactoferrin
- mediators of adhesion of neutrophils to vessel wall
- histamine, complement products (C5a), TNF, IL1, IL8
- transmigration, definition, causes
- passage of activated phagocytes thru vessel wall, promoted by gradients of chemotactic substances like C5a, LTB4 (lipoxygenase pathway metabolite of arachidonic acid), F-met leu phe (bacterial cell wall peptide), IL8
- phagocytosis opsonins
- Fc portion of immunoglobulin, C3b, Mannose
- Products released by phagocytes
- Lysosomal producsts such as elastase, lysosome, collagenase; Nitric oxide; oxygen derived metabolites (i.e. HOOH), HO, superoxide o2-, hypochloruos acid (HOCL)
- Means of activation of complement
- 1) Classic pathway via Cl binding to Fc portion of IgG or IgM, 2) Alternate pathway by bacterial surfaces which stabilize C3b hiding it from serum proteases like factors H and I
- Function of C5a
- 1) vasodilation and increased blood flow, 2) causes phagocytes to produce adhesive surface molecules that allow them to stick to endothelial cells 3) chemotactic peptide for phagocytes, enhances production of mxygen derived metabolites
- C3a function
- vasodilaation and increased blood flow
- C3b function
- opsonin
- major cell types involved in chronic granulomatous inflammation
- mononuclear phagocyts and CD4 T cells
- Types of macrofages
- 1) mobile macrophages, migrate into tissue in response to chemotactic substances 2) splenic macrophages 3) kupffer cells (hepatic macrophages) 4) alveolar macrophages 5) osteoclasts, 6) microglial cells
- CD4 T cell role in granulomatous infections
- produce cytokines like interferon gamma to activate macrophages to kill phagocytized bugs, other CD4 TH1 cytokines drive granuloma formations to keep bug in jail
- Stages of streptococcus pneumonia infection
- 1) complement activation predominately by the alternate pathway 2)C3a & C5a --> local vasodilation and vascular permeability-->exudate 4) at 7 days adaptive immune response w/ IgM and IgG-->classic pathway complement activation--> better opsonisation
- Stages of pulmonary TB
- 1) TB evade intitial inflammatory respnse and PMNs 2) TB multiply in macrophages and travel to lymph nodes 3) Over 2-3 weeks sensitized TH1 CD4 cells specific for TB multiply in lymph nodes and migrate to infected sites 4) produce lymphokines like macrophage activating factor/INF-g/macrophage chemotactic factor-->intracellular killing of TB
- coaches (granulomas)
- sensitized TH1 lymphocytes surrounding granuloma
- mechanism of fever production
- IL1, TNF, IL6 produced by macrophages, endothelial cells, fibroblasts, keratinocytes, lymphocytes,--> cause hypothalamic synthesis of PGE2 raises thermal set point cause vasoconstriction, and shivering (heat conservation and production)
- Systemic manifestations of inflamation
-
1 fever,
2 anemia,
3 neutrophilia,
4 somnolence-malaise, muslce breakdown--wasting--cachexia--anorexia
5 shock, disseminated intravascular coagulation - cause of anemia in inflammation
- decreased erythropoiesis probably due to TNF, interferon, and/or IL1
- Cause of neutrophelia in inflammation
- GM-CSF (granulocyte monocyte-colony stimulating factor) produced by epidermal cells, endothelial cells, and fibroblkasts --> increased production of PMNs and macrophages; parasitic infections -->eosinophilia from (IL5, GM-CSF)
- Somnolence, malaise cause in inflammation
- IL-1, TNF
- Muscle breakdown, wasting, cachexia, anorexia in inflammation
- IL1--> proteolysis thru prostaglandin E2 generation; IL1 decreases appetite by unknown mechanism. IL1 and TNF inhibit enzymes for trigylceride synthesisi
- Shock cause in inflammation
- Massive release of TNF, induces vasodilation and myocardial depression
- Dissemincated intravascular coagulation causes in inflammation
- TNF activates endothelial cells to convert them from a surface which inhibits coagulation to one that promotes clotting; small clots form--consuming clotting factors whle blocking tissue perfusion
- immunodeficiencies that cause susceptibilty to bacterial infection
- 1) few phagocytes (neutropenia) 2) Leukocyte adhesion deficiency 3) antibody deficiency 4) complement C3 deficiency 5) Slow PMN's and macrophages--alcoholic liver disease 6) asplenia
- cause of neutropenia
- 2ndary to chemotherapy
- causes of antibody deficiency
- x-linked agammaglobulinemia rare congenital cause of antibody deficiency 2) acquired antibody deficiency in patients with two B cell malignancies, multiple myeloma and chronic lymphocytic leukemia
- Complement C3 deficiency causes
- congenital C3 deficiency (rare); liver disease (C3 production in liver)
- Slow PMNs and macrophage cause
- alcoholic liver disease
- Asplenia relevence to pneumococcal infection
- 30% pts w/ pneumococcal pneumonia get bugs in blood, splenic macrophages filter them. Asplenia --> may die quickly from overwhelming infection
- Causes of susceptibility to TB
- 1) Not enough CD4 T cells (AIDS, immunosuppressive therapy) 2) geriatric CD$ T cells ; 3) too few macrophages from chemotherapy 4) macrophages not activated (corticosteroid therapy paralyxzes macrophages)
- Outcomes from inflammatory response, examples
- Resolution (pneumococcal pneumonia--macrophages clean debris); 2) scarring, damage (damage from superoxides and enzymes, IL1 and TNF stimulate collagen production--in cystic fibrosis persistant pulmonary inflamation makes destruction of airways) 3) cancer. chronic unresolved infections (osteomyelitis), or infections w/ parasites (Schistosoma Japonicum) may lead to cancer-->superoxides and free radicals damage DNA