Molecular Mediators of Inflammation PDF

Molecular Mediators of Inflammation Unit-II The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. Many mediators have been identified and targeted therapeutically to limit inflammation, like vasoactive amines, lipid products (pro...

Molecular Mediators of Inflammation Unit-II The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. Many mediators have been identified and targeted therapeutically to limit inflammation, like vasoactive amines, lipid products (prostaglandins and leukotrienes), cytokines (including chemokines), and products of complement activation Mediators are either secreted by cells or generated from plasma proteins. Cell-derived mediators are normally sequestered in intracellular granules and can be rapidly secreted by granule exocytosis (e.g., histamine in mast cell granules) or are synthesized de novo (e.g., prostaglandins and leukotrienes, cytokines) in response to a stimulus. Plasma- derived mediators (e.g., complement proteins) are produced mainly in the liver and are present in the circulation as inactive precursors that must be activated, usually by a series of proteolytic cleavages, to acquire their biologic properties. Active mediators are produced only in response to various stimuli like microbial products and substances released from necrotic cells. This ensures that inflammation is normally triggered only when and where it is needed. Most of the mediators are short-lived. They quickly decay, or are inactivated by enzymes, or they are otherwise scavenged or inhibited. There is thus a system of checks and balances that regulates mediator actions. One mediator can stimulate the release of other mediators. For instance, products of complement activation stimulate the release of histamine, and the cytokine TNF acts on endothelial cells to stimulate the production of another cytokine, IL1, and many chemokines. The secondary mediators may have the same actions as the initial mediators but may also have different and even opposing activities. Such cascades provide mechanisms for amplifying—or, in certain instances, counteracting— the initial action of a mediator. Vasoactive Amines: Histamine and Serotonin They are stored as preformed molecules in cells and are therefore among the first mediators to be released during inflammation. 1. Histamine: a. The richest sources of histamine are the mast cells that are normally present in the connective tissue adjacent to blood vessels. It is also found in blood basophils and platelets. b. Histamine is stored in mast cell granules and is released by mast cell degranulation in response to a variety of stimuli, including physical injury, such as trauma, cold, or heat, by unknown mechanisms; binding of antibodies to mast cells, which underlies immediate hypersensitivity (allergic) reactions; products of complement called anaphylatoxins (C3a and C5a) and Neuropeptides (e.g., substance P) and cytokines (IL1, IL8) Antibodies and complement products bind to specific receptors on mast cells and trigger signaling pathways that induce rapid degranulation.  c. Histamine causes dilation of arterioles and increases the permeability of venules. Histamine is considered to be the principal mediator of the immediate transient phase of increased vascular permeability, producing interendothelial gaps in venules. Its vasoactive effects are mediated mainly via binding to receptors, called H1 receptors, on microvascular endothelial cells. The anti-histamine drugs that are commonly used to treat some inflammatory reactions, such as allergies, are H1 receptor antagonists that bind to and block the receptor. Histamine also causes contraction of some smooth muscles. 2. Serotonin: Serotonin (5hydroxytryptamine) is a preformed vasoactive mediator present in platelets and certain neuroendocrine cells, such as in the gastrointestinal tract, and in mast cells in rodents but not humans. Its primary function is as a neurotransmitter in the gastrointestinal tract. It is also a vasoconstrictor, but the importance of this action in inflammation is unclear. Arachidonic Acid Metabolites The lipid mediators prostaglandins and leukotrienes are produced from arachidonic acid (AA) present in membrane phospholipids, and stimulate vascular and cellular reactions in acute inflammation. AA is a 20carbon polyunsaturated fatty acid (5,8,11,14eicosatetraenoic acid) that is derived from dietary sources or by conversion from the essential fatty acid linoleic acid. It does not occur free in the cell but is normally esterified in membrane phospholipids. Mechanical, chemical, and physical stimuli or other mediators (e.g., C5a) release AA from membrane phospholipids through the action of cellular phospholi pases, mainly phospholipase A2. The biochemical signals involved in the activation of phospholipase A2 include an increase in cytoplasmic Ca2+ and activation of various kinases in response to external stimuli. AAderived mediators, also called eicosanoids (because they are derived from 20carbon fatty acids; Greek eicosa = 20), are synthesized by two major classes of enzymes: cyclooxygenases (which generate prostaglandins) and lipoxygenases (which produce leukotrienes and lipoxins) Eicosanoids bind to G protein coupled receptors on many cell types and can mediate virtually every step of inflammation A. Prostaglandins Prostaglandins (PGs) are produced by mast cells, macrophages, endothelial cells, and many other cell types, and are involved in the vascular and systemic reactions of inflammation. They are generated by the actions cyclooxgenases, called COX1 and COX2. COX1 is produced in response to inflammatory stimuli and is also constitutively expressed in most tissues, where it may serve a homeostatic function (e.g., fluid and electrolyte balance in the kidneys, cytoprotection in the gastrointestinal tract). In contrast, COX2 is induced by inflammatory stimuli and thus generates the prostaglandins that are involved in inflammatory reactions, but it is low or absent in most normal tissues. Prostaglandins are divided into series based on structural features as coded by a letter (PGD, PGE, PGF, PGG, and PGH) and a subscript numeral (e.g., 1, 2), which indicates the number of double bonds in the compound. The most important ones in inflammation are PGE2, PGD2, PGF2a, PGI2 (prostacyclin), and TxA2 (thromboxane A2), each of which is derived by the action of a specific enzyme on an intermediate in the pathway. Some of these enzymes have restricted tissue distribution. For example, platelets contain the enzyme thromboxane synthase, and hence TxA2 is the major product in these cells. TxA2, a potent platelet aggregating agent and vasoconstrictor, is itself unstable and rapidly converted to its inactive form TxB2. Vascular endothelium lacks thromboxane synthase but possesses prostacyclin synthase, which is responsible for the formation of prostacyclin (PGI2) and its stable end product PGF1a. Prostacyclin is a vasodilator and a potent inhibitor of platelet aggregation, and also markedly potentiates the permeability increasing and chemotactic effects of other mediators. A thromboxane-prostacyclin imbalance has been implicated as an early event in thrombus formation in coronary and cerebral blood vessels. PGD2 is the major prostaglandin made by mast cells; along with PGE2 (which is more widely distributed), it causes vasodilation and increases the permeability of postcapillary venules, thus potentiating edema formation. PGF2a stimulates the contraction of uterine and bronchial smooth muscle and small arterioles, and PGD2 is a chemoattractant for neutrophils. In addition to their local effects, the prostaglandins are involved in the pathogenesis of pain and fever in inflamma tion. Leukotrienes Leukotrienes are produced by leukocytes and mast cells by the action of lipoxygenase and are involved in vascular and smooth muscle reactions and leukocyte recruitment. There are three different lipoxygenases, 5-lipoxygenase being the predominant one in neutrophils. This enzyme converts AA to 5-hydroxyeicosatetraenoic acid, which is chemotactic for neutrophils, and is the precursor of the leukotrienes. LTB4 is a potent chemotactic agent and activator of neutrophils, causing aggregation and adhesion of the cells to venular endothelium, generation of ROS, and release of lysosomal enzymes. The cysteinyl containing leukotrienes LTC4, LTD4, and LTE4 cause intense vasoconstriction, bronchospasm (important in asthma), and increased permeability of venules. Leukotrienes are more potent than is histamine in increasing vascular permeability and causing bronchospasm. Lipoxins Lipoxins are also generated from AA by the lipoxygenase pathway, but unlike prostaglandins and leukotrienes, the lipoxins suppress inflammation by inhibiting the recruitment of leukocytes. They inhibit neutrophil chemotaxis and adhesion to endothelium. They are also unusual in that two cell populations are required for the trans cellular biosynthesis of these mediators. Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis, and these are converted to lipoxins by platelets interacting with the leukocytes.