Inflammation Lecture 4 PDF

Mediators of Inflammation Lecture 4 Annabel Vila, MD Associate Professor of Pathology Learning objectives 1. Define, list, and describe the general properties of the principal mediators of inflammation. 2. Describe the properties of major vasoactive amines “Histamine & Serotonin” 3. Describe the pro...

Mediators of Inflammation Lecture 4 Annabel Vila, MD Associate Professor of Pathology Learning objectives 1. Define, list, and describe the general properties of the principal mediators of inflammation. 2. Describe the properties of major vasoactive amines “Histamine & Serotonin” 3. Describe the properties of Arachidonic acid metabolites (Prostaglandins, thromboxane, Leukotrienes, and Lipoxins) and list their pharmacologic inhibitors 4. Describes the role of Cytokines (tumor necrosis factor(TNF), and Interleukin-1) and Chemokines. 5. Describe the activation and function of the complement system in inflammation. Opsonization and phagocytosis: This Objective was covered in Lecture 3) 6. Describe other mediators of inflammation: Hageman Factor, platelet-activating factor, Products of coagulation, Kinins, and neuropeptides. Mediators of the inflammatory response Review Question # 1 “Recognition” A 4-year-old child has had a high-volume diarrhea for the past 2 days. On examination she is dehydrated. A stool sample examined by serologic assay is positive for rotavirus. She is treated with intravenous fluids and recovers. Which of the following components is found on intestinal cells and recognizes double-stranded RNA of this virus to signal transcription factors that upregulate interferon production for viral elimination? A. Caspase-1 B. Complement receptor C. Lectin D. T cell receptor E. Toll-like receptor Review Question # 1: correct answer E: Toll-like receptor “Recognition” Toll-like receptors (TLRs) Nonhuman microbial substances such as double-stranded RNA of viruses, bacterial DNA, and bacterial endotoxin, can be recognized by (TLRs) on human cells as part of an innate defense mechanism against infection Where are located the TLRs? Cells of the innate immune system( e.g., macrophages and dendritic cells) Cells of adaptative immunity (e.g., lymphocytes) How are TLRs activated? Pathogens-associated molecular patterns (PAMPs) TLR activation results in the upregulation of NF-kB, (a nuclear transcription factor that activates immune response genes leading to the synthesis of immune mediators) Recognition of microbes and damaged cells Review Question # 1: “other options” Option A: Caspase-1 is activated by an inflammasome complex of proteins responding to bacterial organisms, and produces biologically active interleukin-1 (IL-1). Option B: Complement receptors on inflammatory cells recognize complement components that aid in triggering immune responses through costimulatory signals. Option C: Lectins found on cell surfaces can bind a variety of substances, such as fungal polysaccharides, that trigger cellular defenses. Option D: T cell receptors respond to peptide antigens to trigger a cell-mediated immune response. Review Question # 2 “Mediators of Inflammation: Arachidonic acid (AA) metabolites” A 19-year-old woman develops a sore throat and fever during the past day. Physical examination shows pharyngeal erythema and swelling. Laboratory findings include leukocytosis. She is given naproxen. Which of the following features of the acute inflammatory response is most affected by this drug? A. Chemotaxis B. Emigration C. Leukocytosis D. Phagocytosis E. Vasodilation Review Question # 2 Correct answer: E Naproxen, a nonsteroidal anti-inflammatory drug, targets the cyclooxygenase pathway of arachidonic acid metabolism and leads to reduced prostaglandin generation. Prostaglandins promote vasodilation at sites of inflammation. Chemotaxis is a function of various chemokines, and complement C3b may promote phagocytosis, but neither is affected by aspirin. Leukocyte emigration is aided by various adhesion molecules. Leukocyte release from bone marrow can be driven by the cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF). “Mediators of Inflammation: Arachidonic acid (AA) metabolites” Arachidonic acid (AA) metabolites AA is released from the phospholipid cell membrane by phospholipase A2 and then acted upon by cyclooxygenase or 5-lipoxygenase Cyclooxygenase produces prostaglandins (PG) PGI2,PGD2, and PGE2 mediate vasodilation and ↑ vascular permeability PGE2 also mediates pain and fever 5-lipoxygenase produces leukotrienes (LT) LTB4 attracts activated neutrophils LTC4, LTD4, and LTE4 mediate vasoconstriction, bronchospasm, and ↑vascular permeability Arachidonic Acid Metabolites Review Question # 3: “Mediators of Inflammation: Mast cells” Question # 6: A woman who is allergic to cats visits a neighbor who has several cats. During the visit, she inhales cat dander, and within minutes, she develops nasal congestion with abundant nasal secretions. Which of the following substances is most likely to produce these findings? A. Bradykinin B. Complement C5a C. Histamine D. Interleukin-1 (IL-1) E. Phospholipase C F. Tumor necrosis factor (TNF) Review Question # 3: “Mediators of Inflammation: Mast cells” Correct answer C: Histamine Correct answer C: Histamine It is found in abundance in mast cells, which are normally present in connective tissues next to blood vessels beneath mucosal surfaces in airways. Binding of an antigen (allergen) to IgE antibodies that have previously attached to the mast cells by the Fc receptor triggers mast cell degranulation, with the release of histamine. This response causes increased vascular permeability and mucous secretions Important clinical point The two major vasoactive amines, so named because they have important actions on blood vessels, are histamine and serotonin Review Question # 3: “Mediators of Inflammation: Mast cells” Option A: Bradykinin, generated from the kinin system on surface contact of Hageman factor with collagen and basement membrane from vascular injury, promotes vascular permeability, smooth muscle contraction, and pain. Option B: Complement C5a is a potent chemotactic factor for neutrophils. D and F: Interleukin-1 (IL-1) and tumor necrosis factor (TNF), both produced by activated macrophages, mediate many systemic effects, including fever, metabolic wasting, and hypotension. Option E: Phospholipase C, which catalyzes the release of arachidonic acid, is generated from platelet activation Mediators of Inflammation “Mast cells degranulation releases histamine” Mast cells Widely distributed throughout connective tissue Histamine is stored in mast cell granules and is released by mast cell degranulation in response to a variety of stimuli tissue trauma complements proteins C3a and C5a binding of antigen to IgE antibodies displayed on the surfaces of mast cells, which underlies immediate hypersensitivity (allergic) reactions Neuropeptides (e.g., substance P) Mediators of Inflammation “Mast cells degranulation releases histamine” Histamine function Immediate response Mediate vasodilation of arterioles ↑ vascular permeability (interendothelial gaps in venules) Its vasoactive effects are mediated mainly via binding to receptors on microvascular endothelial cells The antihistamine drugs that are commonly used to treat some inflammatory reactions, such as allergies, are histamine receptor antagonists that bind to and block the receptor Delayed response Production of Arachidonic acid metabolites ( leukotrienes) Mediators of Inflammation Serotonin (5-hydroxytryptamine) Serotonin (5-hydroxytryptamine) Preformed vasoactive mediator present in platelets and certain neuroendocrine cells (GI) Its primary function is as a neurotransmitter in the GI and the CNS It is also a vasoconstrictor, but the importance of this action in inflammation is unclear Review question # 4: “Mediators of Inflammation: Complement” Question # 7: In an experiment, bacteria are inoculated into aliquots of normal human blood that have been treated with an anticoagulant. It is observed that the bacteria are either phagocytized by neutrophils or undergo lysis. Which of the following blood plasma components is most likely to facilitate these effects? A. Complement B. Fibrin C. Kallikrein D. Plasmin E. Thrombin Review question # 4: “Mediators of Inflammation: Complement” correct answer: A: Activation of complement Activation of complement may occur via microbial cell wall components such as polysaccharides (alternative pathway) or mannose (lectin pathway), or antibody attached to surface antigens (classic pathway). A variety of complement components are generated, including complement C5a, a neutrophil chemoattractant; complement C3b, an opsonin; and complement C5-9, the membrane attack complex. Review question # 4: “Mediators of Inflammation: Complement” “other options” The remaining options are more closely associated with coagulation. Option B: Fibrin is generated by the coagulation system, but not with anticoagulation. Option C: Kallikrein may aid in generation of bradykinin and plasmin, but participates just in complement C5a generation. Option D: Plasmin is generated from plasminogen and helps lyse clots. Option E: Thrombin is generated by the coagulation cascade “Mediators of Inflammation: Complement” What is Complement? Proinflammatory serum proteins that “complement” inflammation and circulate as inactive precursors Activation occurs via? Classical pathway: C1 binds IgG or IgM that is bound to antigen Alternative pathway: Microbial products directly activate complement Mannose-binding lectin (MBL) pathway: MBL binds to mannose on microorganisms and activates complement “Mediators of Inflammation: Complement” Complement All pathways result in production of C3 convertase Mediates C3→C3a and C3b, which in turn, produces C5 convertase Mediates C5→C5a and C5b C5b complexes with C6 and C9 to form the membrane attack complex (MAC) Anaphylatoxins: C3a, C4a and C5a Trigger mast cell degranulation, resulting in histamine-mediated vasodilation and ↑ vascular permeability C5a: Chemotactic for neutrophils C3b: Opsonin for phagocytosis MAC: lyses microbes by creating a hole in the cell membrane Biologic activity of the anaphylatoxins “Mediators of Inflammation: Hageman factor “Factor XII” Inactive proinflammatory protein produced in the liver Activated upon exposure to subendothelial or tissue collagen; in turn, activates Coagulation and fibrinolytic systems Complement Kinin system Kinin cleaves high-molecular-weight kininogen (HMWK) to bradykinin, which mediates vasodila on and ↑ vascular permeability (similar to histamine), as well as pain Hageman factor activation and inflammatory mediator production role of Cytokines (tumor necrosis factor(TNF), and Interleukin-1) and Chemokines Cell-Derived Protein Mediators Cytokines: Low–Low-molecular-weight proteins secreted by activated cells Interleukins Growth factors Colony-stimulating factors Interferons Chemokines Class of Cytokine Species Inflammation-Related Actions Interleukins IL-1 IL-6 IL-8 IL-10 IL-13 Inflammatory cell activation Growth Factors GM-CSF M-CSF Stimulate macrophage population Bactericidal activity NK and dendritic cell function Chemokines CC CXC XC CX3C Leukocyte chemotaxis Leukocyte activation Interferons IFNα IFNβ IFNγ Antiviral Leukocyte activation TNFα Fever Anorexia Shock Cytotoxicity Cytokine induction Activation of endothelial and tissue cells Proinflammatory cytokines Central role of interleukin (IL)-1 and tumor necrosis factor (TNF)-α in inflammation