Inflammatory Mediators

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  • Created by: LBCW0502
  • Created on: 25-01-19 10:08
Why is the inflammatory response described as 'a double edged sword'?
Can have beneficial effects but also harm effects
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What is an inflammatory response?
Short term acute response that is defensive and quickly resolved. Innate, non-adaptive, developed early in evolution. Also adaptive immune response
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State the key processes in the inflammatory response
Acute microvascular changes, release of inflammatory mediators, accumulation of inflammatory cells, repair and healing, can also get remodelling and collagen in chronic diseases (graph/diagram, e.g. spot on the face)
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What is an acute inflammatory response?
Microvascular effects triggered from variety of cells and plasma in/around these vessels. Local hormones. Inflammatory mediators released locally at site of infection/inflammation and act locally (tissue injury, pain/inflammation
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Give examples of inflammatory mediators
Histamine (amine). Bradykinin (peptide). Nitric oxide. Eicosanoid - lipid (prostaglandin, leukotrienes). Neuropeptides (peptides e.g. SP). Complement pathway - peptides (C5a). Cytokines peptides - IL-1. Chemokines
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Describe features of the microcirculation
Arterioles (smooth muscle, relax/contract, vasodilation/increased blood flow during inflammation). Post-capillary venules (leaky, plasma protein fluids released for oedema formation, cell accumulation). Capillaries (transport nutrients, gas exchange)
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Describe the features of increased blood flow
Activity in arteriole. Sensory nerve can release inflammatory mediators. Mast cells outside arterioles (can release mediators).
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What are the sources of vasodilators?
From endothelial cells and inflammatory cells - prostaglandins, NO. From sensory nerves - neuropeptides (e.g. CGRP)
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Describe features of increased microvascular permeability (1)
Post-capillary venule. Odema formation (due to plasma extravasation - plasma goes out into extracellular tissue). Endothelial cells become unstuck (adhesion molecules apart) or actin/myosin contract (gaps)
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Describe features of increased microvascular permeability (2)
Neutrophil dependent microvascular permeability (agents that stimulate neutrophil activation). Direct acting (histamine, SP, bradykinin, PAF, leukotrienes)
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What is the issue with patients with fluid in lungs?
Difficult to balance fluid in lungs due to oedema formation
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Describe features of neutrophil-endothelial cell interactions
Roll along endothelial cells within post-capillary venule. Cell adhesion molecules expressed on endothelial cells. Neutrophil flattens (adherence). Emigrates out (extravasation). Senses bacteria (phagocytosis) - chronic inflammatory/harmful effects
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Give examples of mediators that lead to neutrophil accumulation in tissues
Neutrophil activating agents (LBT4, C5a, IL-8). Endothelial adhesion molecule stimulants (TNF, IL-1)
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Describe features of histamine (1)
Formed from histidine. Major source - mast cells/basophils. Preformed, released in allergic/hypersensitivity (IgE) responses
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Describe features of histamine (2)
Act on H1 receptors (located on endothelial cells, line post capillary venules). Act to increase blood flow (contract/make gaps), increases microvascular permeability and itch
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Describe features of antihistamines
Chlorpheniramine. Non sedating ones preferred today/patient preference - terfenadine (interaction in heart if patient has grapefruit/acidic fruit), cetirizine (OTC), astemizole (OTC). Allergy, hay fever and skin irritations
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Describe features of bradykinin (1)
Peptide formed in plasma by activity of enzymes on tissue fluid substrates (kininogens) in acute inflammatory response. Metabolised by ACE and carboxypeptidases (ACE-I - side effect of cough due to bradykinin)
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Describe features of bradykinin (2)
(carboxypeptidases take off terminal amino acid). Bradykinins are present in nasal cavity during allergic rhinitic attacks
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Describe features of bradykinin (3)
Bradykinin acts on B2 receptors - mediate increased blood flow, increased microvascular permeability, nociception, bronchoconstriction and nasal blockage
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Describe features of bradykinin antagonists
B2 antagonists inhibit effect of some angioedemas (from side effects of some drugs). B1 receptors are induced in inflammation and mediate similar responses (e.g. pain)
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Standard emergency treatment of ACE-I induced angioedema consists of what?
Symptomatic treatement with glucocorticoids and antihistamines. This form of angioedema is not a histamine-mediated reaction (patients don't respond well to therapy). Icatibant
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What is the complement pathway (classical pathway)?
Immune pathway, activated by immune complexes (IgG or IgM)
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What is the complement pathway (lectin pathway)?
Activated by microbes - carbohydrates (e.g. mannin binding lectin complex)
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What is the complement pathway (alternative pathway)?
Activated by pathogens on cell surface
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What is the complement pathway (C3 for inflammation)?
Peptide cleaved to form C3a and C5a (mediates influence mast cell activation, anaphylatoxin and neutrophil accumulation) - medicines under development
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What is the complement pathway (C3 for opsonization)?
C3 cleaved to form C4b and C3b (bind complement receptors and mediate uptake by phagocytes, facilitate phagocytosis)
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What is the complement pathway (C3 for lysis)?
C3 cleaved to form C5, C6, C7, C8, C9 (C5b-9 is the membrane attack complex and mediated lysis of pathogens and cells)
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Describe the metabolism of arachidonic acid
Can be metabolised by cyclo-oxygenase to produce prostaglandins and thromboxanes (vasodilator, increase pain sensation and induce fever). Can be metabolised by lipoxygenase to form leukotrienes (increase oedema formation/some are bronchoconstrictors)
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Describe features of mediators and arthritis (1)
High doses of PGs produced. TNF alpha (cytokine produced at early onset of arthritis, from inflammatory cells/synovial pannus - changes to become inflammatory cell, also produces IL-1)
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Describe features of mediators and arthritis (2)
TNF alpha and IL-1 synergistically support each other to cause more mediator release (IL-6, IL-8, IL-17 - pro-inflammatory, IL-10 - anti-inflammatory)
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Describe features of mediators and arthritis (3)
Can get balance between pro/anti-inflammatory mediators (high/low)
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Describe features of cytokines and chemokines (1)
Peptides/proteins (major mediators in chronic conditions). Secreted by cells (inflammatory cells - macrophages/mast cells/neutrophils when activated). Diverse activity/some potent (arthritis). Pro/anti-inflammatory. Act on specific receptors
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Describe features of cytokines and chemokines (2)
Potent in small amounts. Act synergistically (additive effect). Can cause a cytokine storm (conflict IL-10, IL-17)
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Outline features of a cytokine storm (anti-inflammatory mediators outnumbered)
Micro-organism/endothelial cells release cytokines. Macrophages release activated T-cells, activated macrophages/neutrophils, leads to cytokine storm (and necrosis of neutrophils) - acute respiratory distress syndrome (whole body activated)
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Describe features of tumour necrosis factors and interleukins (1)
TNF alpha (role in chronic inflammation, stimulates emigration of inflammatory cells e.g. neutrophils and macrophages, secretion of other cytokines)
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Describe features of tumour necrosis factors and interleukins (2)
IL-1 and TNF combine to influence events. IL-1/6/7 (pro-inflammatory (leucocyte accumulation, systemic response). IL-2 (t-cell activation). IL-3 (bone marrow stimulant). IL-5 (eosinophil activity/low conc. IL-10 (anti-inflammatory)
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Describe features of interferons, colony stimulating factors and chemokines (1)
Interferons (IFNs) interfere with viral application (alpha/beta/gamma). Colony stimulating factors (CSF) - growth, maturation, leukocytes, blood vessels
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Describe features of interferons, colony stimulating factors and chemokines (2)
Chemokines (smaller peptides). Chemoattractant (causes inflammatory cells to come to site of inflammation, attract leukocytes to inflammation/out of vessels and into tissue, bind to GCPRs)
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Describe features of interferons, colony stimulating factors and chemokines (3)
Chemokines based on structure (disulfide bonds, CC, C, CXC, CX3). Monocyte-chemoattactant protein 1 (MCP-1 or CCL2). RANTES/CCL-5 (t-cells, eosinophils, basophils). IL-8 - neutrophils. Research/new treatments discovered
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What are the pro-inflammatory mediators in chronic inflammation?
TNF alpha, IL-1, IFN gamma, GM-CSF, IL-8, chemokines, IL-15/16/17/18, TGF beta, IL-6 (targets in psoriasis/diagram)
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What are the anti-inflammatory mediators in chronic inflammation?
IL-1RA, sIL-1R1, sTNF-R, monoclonal antibody to TNF, IL-4/10/11/12/18BP (targets in psoriasis/diagram)
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Describe features of TNF alpha (1)
Released from macrophages when activated. Stimulate production of other cytokines, chemokine production, adhesion molecules (E-selectin, VCAM-1), increase VEGF (cause angiogenesis/growth of new blood vessels). Increased inflammation/cell infiltration
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Describe features of TNF alpha (2)
Mediators can act on keratinocytes hyperproliferation, hepcidin inclusion, PGE, osteoclast activation (resorption), chrondocyte activation (metailoproteinase production, cartilage destruction), exacerbate Th-1 inflammatory response in gut
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Describe features of TNF alpha (3)
Processes result in psoriasis, RA and Crohn's disease
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