Synthesis of Mediators

Chapter 6 This chapter outlines the concepts of innate immunity, inflammation, and wound healing. Innate immunity refers to the body's initial defense mechanisms against invasion and injury. Inflammation is the body's response to injury and infection, aimed at protecting and healing the body. Wound healing involves several phases, including hemostasis, inflammation, tissue formation, and remodeling. Bullet points Antihistamines  Drugs that block histamine receptors, resulting in decreased vascular effects Histamine effects  Contraction of smooth muscle cells, including bronchial smooth muscles seen in asthma  Contraction and increased permeability of endothelial cells  Increased chemotaxis in neutrophils  Prostaglandin synthesis in mast cells Histamine receptors  H1 receptor present on smooth muscle cells  H2 receptor abundant on parietal cells of stomach mucosa  Both receptors are distributed among various immune cells and have different effects  Stimulation of H1 receptors on neutrophils increases chemotaxis, while H2 receptor stimulation inhibits it Chemotactic factors and mediators produced by mast cells  Mast cell granules contain chemotactic factors like neutrophil chemotactic factor (NCF) and eosinophil chemotactic factor of anaphylaxis (ECF-A)  Leukotrienes induce smooth muscle contraction and increased vascular permeability  Prostaglandins cause increased vascular permeability, neutrophil chemotaxis, and pain Synthesis of mediators  Activated mast cells initiate synthesis of leukotrienes, prostaglandins, and platelet-activating factor  Leukotrienes have slower and more prolonged inflammatory responses compared to histamine  Prostaglandins cause pain and have various effects on inflammation Inhibition of COX-1 and COX-2  Some drugs can inhibit COX-1 and/or COX-2  Inhibition of COX-1 can cause undesirable side effects, particularly in the gastrointestinal (GI) system  Aspirin and other NSAIDs inhibit both COX-1 and COX-2, leading to potential GI bleeding  Selective COX-2 inhibitors may offer a better GI effect profile  All COX inhibitors have an increased risk for cardiovascular disease due to their effects on blood vessels and clotting Platelet-activating factor (PAF)  PAF can be produced by various cells including neutrophils, monocytes, endothelial cells, mast cells, and platelets  PAF's biological activity is similar to that of leukotrienes  PAF can cause endothelial cell retraction, increased vascular permeability, leukocyte adhesion, platelet activation, and mast cell activation Endothelial cells  Endothelial cells line blood vessels and regulate circulation and movement of water and solutes between blood and tissues  They prevent spontaneous activation of platelets and clotting when there is no tissue injury  During inflammation, damaged endothelial cells expose the prothrombogenic subendothelial connective tissue matrix, initiating platelet activation and clot formation  Endothelial cells promote recruitment and invasion of leukocytes during inflammation  They also play a role in angiogenesis and wound healing Platelets  Platelets are anucleated fragments formed from megakaryocytes  They circulate until activated by vascular injury  Platelets can be activated by tissue destruction and inflammation, releasing biochemical mediators and synthesizing thromboxane A2 (TXA2)  Platelets contribute to coagulation, inflammation acceleration, pathogen recognition and killing, and wound healing promotion Neutrophils  Neutrophils are the predominant phagocytes in early inflammation  They are attracted and activated by various inflammatory mediators  Their primary role is phagocytosis of microbes and removal of cellular debris and dead cells  Neutrophils have a short lifespan and become part of the pus removed from the body or drained from infected sites White Blood Cells and Immune Response  There are different types of granulocytes, including neutrophils, eosinophils, and basophils  Neutrophils are the most prevalent and are phagocytic cells that perform antimicrobial functions  Eosinophils serve as defense against parasites and regulate vascular mediators released from mast cells  Basophils release histamine and are involved in allergies and asthma  Monocytes are large white blood cells produced in the bone marrow and transform into macrophages at the site of inflammation  Macrophages play a crucial role in the inflammatory response, including phagocytosis, tissue healing, and removal of debris  Dendritic cells link the innate and adaptive immune responses by presenting invaders to T lymphocytes  Lymphocytes include B and T cells, which produce antibodies and regulate immune cells, respectively  Natural killer cells eliminate virally infected and cancerous cells Phagocytosis process  Phagocytosis is the ingestion of microbes, foreign particles, or cell fragments  Neutrophils and macrophages are the main phagocytes for phagocytizing pathogens or damaged cells  Neutrophils are attracted to the area of injury by chemotactic factors  Adhesion molecules increase the "stickiness" of neutrophils to the endothelial cell wall Steps of phagocytosis  Recognition and adherence of the phagocyte to its target  Engulfment (ingestion or endocytosis) and formation of phagosomes  Fusion of the phagosome with lysosomal granules within the phagocyte  Destruction of the target Phagocytosis of a red blood cell  Red blood cells attach to the surface of a macrophage  The macrophage membrane encloses the red cell  The red blood cells are engulfed by the macrophage Opsonization and Phagocytosis  Opsonins (e.g., C3b and antibodies) enhance adherence of phagocytes to microorganisms or cells  Engulfment (endocytosis) occurs when pseudopods surround the target, forming a phagosome  Lysosomes fuse with the phagosome to create a phagolysosome where target destruction occurs Mechanisms of Microbial Killing  Oxygen-dependent mechanisms involve the production of toxic oxygen species  Oxygen-independent mechanisms include acidic pH, cationic proteins, enzymatic attack, and lactoferrin binding of iron