Acute Inflammation BMS150 PDF

Acute inflammation How do we get from here… To here? Steps of Acute Inflammation A. Alteration of vascular caliber - vasodilation Leads to increases in blood flow at the capillary bed due to arteriolar dilation, dilation of precapillary sphincters § Nitric oxide and histamine A variety of prostaglan...

Acute inflammation How do we get from here… To here? Steps of Acute Inflammation A. Alteration of vascular caliber - vasodilation Leads to increases in blood flow at the capillary bed due to arteriolar dilation, dilation of precapillary sphincters § Nitric oxide and histamine A variety of prostaglandins (PGI2, PGE2, PGD2) Platelet activating factor (at low concentrations – higher concentrations cause vasoconstriction) Complement § C5a and C3a stimulate histamine release At low concentrations, nitric oxide is a potent vasodilator (why Viagra is a profitable drug) At high concentrations, it’s capable of destroying both microbes and host cells since it’s a free radical Higher concentrations produced by an inducible nitric oxide synthase in macrophages Vasodilation Arterioles and pre-capillary sphincters dilate leading to vastly increased blood flow in inflamed tissue Vasodilation and fluid loss (due to increased permeability) lead to slower blood flow § Known as vascular congestion § This helps with margination of leukocytes Whoa… what do we need to know from that last slide? Prostaglandins and leukotrienes are produced when PLA2 generates arachidonic acid from membrane phospholipids Different types of cyclooxygenases produce different types of prostaglandins from arachidonic acid § Important prostaglandins – PGE2, PGD2, and PGI2 cause vasodilation and increase vascular permeability, important acute inflammatory mediators Different types of 5-lipoxygenase produce different types of leukotrienes from arachidonic acid that seem particularly important in lung tissue § LTB4 – important chemotactic agent § Other LTs – increased vascular permeability and smooth muscle constriction (think asthma) Lipoxins are generated from arachidonic acid by 12lipoxygenase – they decrease inflammation Steps of acute inflammation B. Enhancement of vascular permeability Capillaries and venules become more “leaky” with the release of a number of mediators § § Histamine and serotonin (released by activated platelets, a link between inflammation and clotting) Prostaglandins (PGD2 and PGE2) Leukotrienes (LTC4, LTD4, LTE4) Platelet activating factor C3a and C5a Bradykinin a wide variety of proteins and mediators can enter the interstitial space from the bloodstream Vascular permeability Increased vascular permeability is due to contraction of endothelial cells Occurs mainly in venules Often short-lived Another mechanism is endothelial damage Can be caused by trauma, burns, microbial damage Can also be caused by leukocyte-mediated damage to the endothelium (often longer-lived) Increased transcytosis can also result in leakage of plasma components into the interstitial space Transcytosis? Active, vesicle-mediated transport across the capillary endothelial cell Large molecules can move across the endothelium via: Pinocytosis (caveolin pathway) Receptor-mediated endocytosis Mechanisms of increased vascular permeability Lymphatics As interstitial fluid accumulates during inflammation, pressure increases in the interstitial space and lymphatic drainage increases § Normally only a small amount of interstitial fluid is produced in non-inflamed tissue § Excess fluid, microbes, debris, and leukocytes all migrate into the lymph during inflammation The lymphatic vessels themselves can become inflamed – known as lymphangiitis Leukocyte migration C. Emigration and activation of leukocytes § § Neutrophils, monocytes, eosinophils, and basophils will all migrate from the circulation into inflamed tissue Steps: a) b) c) d) e) Margination Mediated by binding of selectins and Rolling cellular adhesion molecules to their Adhesion respective ligands on leukocytes Diapedesis Chemotaxis of leukocytes to sites of injury or infection Chemokine or cytokine? Cytokine – a (small) protein messenger, secreted by a vast array of cells, that can: § Influence the differentiation of a wide variety of cells, including leukocytes § Mediate – activate or inactivate – the activity of many cells, including leukocytes § Increase or decrease the production of a wide variety of stem/hematopoietic cells Chemokine – structurally-related family of small cytokines that: § Bind to cell-surface receptors (usually leukocytes) § Induce movement of leukocytes along the chemokine concentration gradient § Mediate adhesion of leukocytes for the purposes of: Differentiation Inflammation/migration Chemokines 2 major chemokine families § CXC CXC chemokines attract neutrophils, are angiogenic, and are very similar in structure The “X” indicates the location of a disulphide bond § CC Act on/attract a wide variety of other leukocytes Chemokines - FYI Leukocyte migration C. Emigration and activation of leukocytes § Steps: a) Margination – leukocytes migrate towards vessel wall b) Rolling – formation & dissociation of adhesion bonds between leukocytes and endothelial cells *Activation by chemokines presented on endothelial cells is required before the leukocyte can form stable adhesion Endothelial cell presents a chemokine that stimulates activation of the leukocytes This increases affinity of leukocyte integrin for it’s ligand, allowing stable/tight adhesion bonds to form Leukocyte migration C. Emigration and activation of leukocytes § Steps continued: c) Stable/Tight Adhesion – Formation of tight/stable adhesion bonds between leukocytes and endothelial cells d) Diapedesis/ Transmigration – leukocyte migrates through endothelium e) Chemotaxis of leukocytes to sites of injury or infection Putting it all together Adhesion molecules and their ligands – what are the concepts here? A variety of inflammatory mediators increase the ability of leukocytes to migrate to a target Histamine, Thrombin Rolling Selectin expression by endothelial cells TNF & IL1 ICAM expression by endothelial cells Chemokines Increased integrin affinity Chemotactic agents All of these agents are produced in higher concentrations at sites of cellular damage/pathogen invasion Leukotriene B4 Bacterial products containing N-formyl-methionine Activated complement (particularly C5a) More on this in the e-module Chemokines (IL-8, RANTES, eotaxin) Leukocytes can “follow the breadcrumbs” to the site of pathology via the chemotactic agent concentration gradient For leukocyte emigration: What molecules cause loose adhesion of leukocytes to the vascular endothelium? § What binds to what? How about tight adhesion? § What cells are integrins found on? How about ICAMS? What causes expression of the molecules above? What is the role of a chemokine in: § Tight adhesion? § Migration of a leukocyte to a site of inflammation? What is a chemotactic agent? Name a few