Inflammation and Repair L3 PDF

Inflammation and Repair L3 1. LEUKOCYTE-MEDIATED TISSUE INJURY 2. MEDIATORS  Leukocyte-Mediated Tissue Injury Leukocytes are important mediators of injury to normal cells and tissues under several circumstances. As part of a normal defense reaction against...

Inflammation and Repair L3 1. LEUKOCYTE-MEDIATED TISSUE INJURY 2. MEDIATORS  Leukocyte-Mediated Tissue Injury Leukocytes are important mediators of injury to normal cells and tissues under several circumstances. As part of a normal defense reaction against infectious microbes, when tissues at or near the site of infection suffer collateral damage (‫)ضرر جانبي‬. Examples: 1. In some infections that are difficult to eradicate, such as tuberculosis and certain viral diseases such as hepatitis, the prolonged host response contributes more to the pathology than does the microbe itself. 2. When the inflammatory response is inappropriately directed against host tissues, as in certain autoimmune diseases. 3. When the host “hyper-reacts” against usually harmless environmental substances, as in allergic diseases, including asthma, and some drug reactions. 2  Leukocytes Damage Tissues by Releasing Injurious Molecules The potentially toxic contents of granules are released by leukocytes into the extracellular milieu by several mechanisms. Controlled secretion of granule contents following degranulation is a normal response of activated leukocytes. 1) If phagocytes encounter materials that cannot be easily ingested, such as immune complexes deposited on immovable flat surfaces (e.g., glomerular basement membrane), the inability of the leukocytes to surround and ingest these substances ( ‫“محبط‬frustrated phagocytosis”) triggers strong activation and also the release of large amounts of granule enzymes into the extracellular environment. 2) Some phagocytosed substances, such as urate and silica crystals, may damage the membrane of the phagolysosome and also lead to the release of damaging contents. 3  Termination of the Acute Inflammatory Response Such a powerful system of host defense, with its inherent capacity to cause tissue injury, needs tight controls to minimize damage. In part, inflammation declines after the offending agents are removed simply because the mediators in rapid bursts, only as long as the stimulus persists, have short half-lives, and are degraded after their release. Neutrophils also have short half-lives in tissues and die by apoptosis within hours to a day or two days after leaving the blood. 4  Termination of the Acute Inflammatory Response In addition, as inflammation develops, the process itself triggers a variety of stop signals that actively terminate the reaction. These active termination mechanisms include a switch in the type of some products of macrophages and other cells from inflammation-induced substances to anti- inflammatory agents. Other control mechanisms that have been demonstrated experimentally include neural impulses (cholinergic discharge), which inhibit the production of TNF in macrophages. (Cholinergic: relating to nerve cells in which acetylcholine acts as a neurotransmitter). 5 Other Functional Responses of Activated Leukocytes(1-2) In addition to eliminating microbes and dead cells, activated leukocytes play several other roles in host defense. Importantly, these cells, especially macrophages, produce: (a) Cytokines that can either amplify or limit inflammatory reactions, (b) Growth factors that stimulate the proliferation of endothelial cells and fibroblasts and the synthesis of collagen. (c) Enzymes that remodel connective tissues. In addition to these activities, macrophages also have important roles in orchestrating chronic inflammation and tissue repair, after the inflammation has subsided. 6 Other Functional Responses of Activated Leukocytes (2-2) Beside the importance of neutrophils and macrophages, it has become clear that some T lymphocytes, which are cells of adaptive immunity, also contribute to acute inflammation. The most important of these cells are those that produce the cytokine IL-17 (so-called “TH17 cells”). IL-17 induces the secretion of chemokines that recruit other leukocytes. In the absence of effective TH17 responses, individuals are susceptible to fungal and bacterial infections. 7  MEDIATORS OF INFLAMMATION The mediators of inflammation are the substances that initiate and regulate inflammatory reactions. Our knowledge on the mediators has been used to produce anti-inflammatory agents that are used every day by many people and which include familiar drugs such as aspirin and acetaminophen. 8 MEDIATORS OF INFLAMMATION 9 Some Features of Mediators (1-3) (4 Main Features) 1. Mediators may be produced locally by cells at the site of inflammation, or they may be circulating in the plasma (typically synthesized by the liver) as inactive precursors that are activated at the site of inflammation. A. Cell-derived mediators : are either: normally sequestered (seized) in intracellular granules and are rapidly secreted upon cellular activation (e.g., histamine in mast cells) or are synthesized in response to a stimulus (e.g., prostaglandins and cytokines). B. Plasma-protein-derived mediators: (complement proteins, kinins) typically undergo proteolytic cleavage to acquire their biologic activities. 10 Some Features of Mediators(2-3) (4 Main Features ) 2. Most mediators induce their effects by binding to specific receptors on target cells. Mediators may act on only one or a very few targets, or they may have widespread actions, with differing outcomes depending on which cell type they affect. Some mediators have direct enzymatic and/or toxic activities (e.g., lysosomal proteases and ROS). 11  Some Features of Mediators (3-3) 3. Mediators may stimulate target cells to release secondary effector molecules. Different mediators may have similar actions, in which case they may amplify a particular response, or they may have opposing effects, thus serving to control the response. 4. The actions of most mediators are tightly regulated. Once activated and released from the cell, mediators quickly decay, inactivated by enzymes, eliminated or are inhibited. 12  Cell-Derived Mediators: Which cells? Tissue macrophages, mast cells, and endothelial cells at the site of inflammation, as well as leukocytes that are recruited to the site from the blood, are all capable of producing different mediators of inflammation. 13  Major Cell-derived Mediators of Inflammation (6 types) (1-2) 1. Vasoactive amines: histamine, serotonin; main effects are vasodilation and increased vascular permeability. 2. Arachidonic acid metabolites: prostaglandins and leukotrienes; several forms exist and are involved in vascular reactions, leukocyte chemotaxis, and other reactions of inflammation; antagonized by lipoxins. 14  Major Cell-derived Mediators of Inflammation (6 types) (2-2) 3. Cytokines: proteins produced by many cell types; usually act at short range; mediate multiple effects, mainly in leukocyte recruitment and migration; principal ones in acute inflammation are TNF, IL-1, and chemokines. 4. Reactive oxygen species: role in microbial killing, tissue injury 5. Nitric oxide: vasodilation, microbial killing. 6. Lysosomal enzymes: role in microbial killing, tissue injury 15 The principal chemical mediators of inflammation. EC, Endothelial cells. 16  ‫ لالطالع‬Role of Mediators in Different Reactions of Inflammation Reaction Mediators Vasodilation Prostaglandins, Nitric oxide, Histamine Increased vascular permeability Histamine and serotonin C3a and C5a (by liberating vasoactive amines from mast cells, other cells) Bradykinin Leukotrienes C4, D4, E4 PAF Substance P Leukocyte recruitment and TNF, IL-1 activation Chemokines C3a, C5a Leukotriene B4 (Bacterial products, e.g., N-formyl methyl peptides) Fever IL-1, TNF, Prostaglandins Pain Prostaglandins , Bradykinin, Neuropeptides Tissue damage Lysosomal enzymes of leukocytes, Reactive oxygen species, Nitric oxide 17  Cell-Derived Mediators: Vasoactive Amines : (1-2) Histamine A) Histamine It is produced by many cell types, particularly mast cells adjacent to vessels, as well as circulating basophils and platelets. Preformed histamine is released from mast cell granules in response to a variety of stimuli including trauma, immune reactions and others. In humans, histamine causes arteriolar dilation and is the principal mediator of the immediate phase of increased vascular permeability, inducing venular endothelial contraction and interendothelial gaps. Soon after its release, histamine is inactivated by histaminase. 18  Cell-Derived Mediators: Vasoactive Amines:(2-2) Serotonin B) Serotonin (5-hydroxytryptamine) It is also a preformed vasoactive mediator, with effects similar to those of histamine. It is found primarily within platelet dense body granules (along with histamine, adenosine diphosphate, and calcium) and is released during platelet aggregation. 19  Summary : (1-2) Plasma Protein-Derived Mediators of Inflammation Circulating proteins of three interrelated systems (the complement, kinin, and coagulation systems) are involved in several aspects of the inflammatory reaction. 1. Complement proteins: Activation of the complement system by microbes or antibodies leads to the generation of multiple breakdown products, which are responsible for leukocyte chemotaxis, opsonization and phagocytosis of microbes and other particles, and cell killing. 20  Summary : (2-2) Plasma Protein-Derived Mediators of Inflammation 2. Coagulation proteins: Activated factor XII triggers the clotting, kinin and complement cascades, and activates the fibrinolytic system. 3. Kinins: Produced by proteolytic cleavage of precursors; mediate vascular reaction, pain. 21  Thank you Wednesday, October 16, 2024 22