Acute Inflammation Mediators PDF

Acute inflammation (III) Mediators of inflammation Textbook chapter 3 Pgs 70-78 Objectives To : ❖List select mediators of Acute Inflammation ❖Describe mechanisms of action of select mediators of Acute Inflammation ❖Recognize the role of mediators in clinical expression of inflammation ❖Describe asso...

Acute inflammation (III) Mediators of inflammation Textbook chapter 3 Pgs 70-78 Objectives To : ❖List select mediators of Acute Inflammation ❖Describe mechanisms of action of select mediators of Acute Inflammation ❖Recognize the role of mediators in clinical expression of inflammation ❖Describe associated pathways for modulating inflammatory response Inflammation Overview Recognition Recruitment & Vascular changes Removal Regulation Repair / Resolution Overview: Chemical Mediators Are plasma proteins or released by host cells in response to stimuli Cell derived mediators may be sequestered within granules and rapidly secreted or synthesized de novo Mostly macrophages, mast cells, endothelial cells and recruited leukocytes Plasma derived mediators are circulating in the plasma in precursor form and undergo proteolytic cleavage to become active at the site of inflammation Induce inflammatory response by: recruiting circulating leukocytes activating leukocytes to enhance ability to remove offending agent action on vasculature Bind specific receptors on target cells May amplify or help diminish a particular response Are tightly regulated- decay quickly, are inactivated or eliminated Mediators of Inflammation Cell derived mediators: Pre-formed within cells ❖Histamine ▪mast cells, and blood basophils & platelets ▪in response to physical injury, cold or heat, binding of antibodies (allergy), products of complement (C5a, C3a), Subst P, IL-1, IL-8 ▪Vasodilation (arterioles), Increased vascular permeability (venules), and endothelial activation, weak smooth muscle contraction ❖Serotonin ▪Platelets (also GI & CNS) ▪Vasoconstrictor (venules) ❖Lysosomal enzymes/ROS ❖phagocytes ❖Neuropeptides (Subst P) Substance P enhances (almost) all inflammatory pathways (cellular) in addition to CNS effects ▪ From sensory nerve fibers, central AND periphery ▪ First responder in injury to ↑ protective (inflammatory) mechanisms ▪ Act on: leukocytes, endothelial cells, © "Biological Sealing and Defense in Peri-Implant Mucosa other neurons, keratinocytes, fibroblasts Mechanisms of Dental Implants". Yamaza & Kido ▪ in skin, muscle, joints, lungs, GI tract In book: Implant Dentistry 2021 ▪ → Vasodilation (axon reflex & NO), ↑Cytokines, modulate pain* ▪ Molina-Ortega F, et all, Immediate effects of spinal manipulation on nitric oxide, substance P and pain perception, Man Ther 2014; 19(5):411-7. * manipulation was NOT on a subluxation but on the same joint in all subjects increased pressure pain thresholds (0 and 2 h after intervention) and increase in substance P plasma level in the cervical manipulation group → analgesia WHY?? Cell derived mediators: newly synthesized Arachidonic acid and its metabolites (Eicosanoids) Action Eicosanoid Vasodilation Prostaglandins PGI2 (prostacyclin), PGE1, PGE2, PGD2 Vasoconstriction Thromboxane A2, leukotrienes C4, D4, E4 Increased vascular permeability Leukotrienes C4, D4, E4, Prostaglandins PGE2, PGD2, Chemotaxis, leukocyte adhesion Leukotrienes B4, HETE Decrease pain, improve mood Anandamide, endocanabinoids Cytokines Interleukins ( 1, 6, 8, 17) Tumor necrosis factor α (TNFα) Chemokines Colony stimulating factors Platelet activating factor (PAF) – lipid mediator Endothelial cells contain prostacyclin synthase: PGI2 (dilation) Platelets contain thromboxane synthase: TXA2 (constriction) Prostaglandins are also involved in pain and fever and systemic effects LTB4 is powerful chemotactant for neutrophils Lipoxins limit the inflammation - to produce them Leukocytes, particularly neutrophils, produce intermediates in lipoxin synthesis, and these are converted to lipoxins by platelets interacting with the leukocytes. Platelet Activating Factor (PAF) ▪ from phospholipids of platelets, neutrophils, endothelial cells, monocytes, basophils & some bacterial phospholipids ▪ At low concentrations (i.e. at the beginning of the inflammatory process): vasodilation and increased vascular permeability (up to 1000 X more potent than histamine) (may induce shock) ▪ Platelet activation /degranulation & aggregation (thrombosis) ▪ Leukocyte adhesions, chemotaxis, degranulation (inflammation) ▪ Increased pain ▪ vasoconstriction, and bronchospasm (aggravates asthma) Cytokines Interleukins ( 1, 6, 8) Tumor necrosis factor TNF α Chemokines Colony stimulating factors Injury Activation of Macrophages Tumor Necrosis Factor (TNF) and Interleukin 1(IL-1) Systemic Effects Leukocyte Effects Endothelial effects Fibroblast effects Fever Increased cytokine production Leukocyte adherence Proliferation Increased procoagulant activity Production of collagen Decreased anticoagulant activity Production of collagenase and protease Increased Sleep Decreased appetite Production of Acute Phase Proteins Neutrophil Leukocytosis Insulin resistance Production of interleukins 1,8,6 Production of Platelet Derived Growth Factor Plasma-derived factors  produced in the liver  Acute phase proteins (e.g. C Reactive Protein)  Coagulation factor XII & products of coagulation  Complement  Kinines Factor XII (Hageman factor) Collagen, Basement membrane, Activated platelets Factor XIIa (activated Factor XII) KininCascade cascade Kinin Kallikrein Coagulation Cascade cascade Coagulation Fibrinolytic Fibrinolyticsystem system kallikrein, a chemotactant is also an activator of factor XII HMWK bradykinin leads to increased vascular permeability, bronchial smooth muscle contraction and arteriole vasodilation and produce pain Bradykinin Plasmin Complement cascade Thrombin Fibrin clotting pathway Fibrinogen Fibrin split products Complement Pathway Action Vasoconstriction Mediators/Triggers Norepinephrine, Mechanical Stress, cold;. TX A , LTC , D , E Histamine, PAF (low conc), NO, Subst P, Heat; PGI (prostacyclin) &other PG Histamine; C3a, C5a. Mechanical Stress PGE , PGD LTC , D , E Vascular endothelial growth factor (VEGF) Tryptase; Matrix metalloproteinases (MMPs) TNF, IL-1,-6, -8; C3a, C5a LT B , HETE 2 Vasodilation 4 4 4 2 Increased vascular permeability Chemotaxis, leukocyte adhesion 2 2, 4 4 4 4 Bronhoconstriction PGE2, PGF2, LTC , D , E Pain Bradikinin, PAF, PGE2 Mechanical/thermal/electrical stimuli Fever PGE2, IL-1,-6, TNF, LPS Tissue damage Free radicals (ROS & ONOO) Lysosomal enzymes (Mcf, PMN) 4 4 4 C3,5 complement components, IL interleukine, LPS: Lypopolysaccharide (from G- bacteria), Mcf: macrophages, NO nitric oxide, ONOO: peroxynitrite, PAF: platelet activating factor, PG prostaglandin, PMN: neutrophils /polymorphonuclear, ROS reactive oxygen species, TNF tumor necrosis factor, TX: tromboxanes, Modulation of inflammatory cell activity  Inhibition of cell activity:  cAMP (PGI2,lipoxines),  α1-adrenergic (IP3)  cholinergic (ion channels or G protein)  Enhancement:  cGMP (TxA2 , most PG, IL, CK),  Specific protein pathways (IL, TNF)  b1 adrenergic on neutrophyls (chemotaxis, cAMP),  Substance P (clatrin internalization),  Piezo1 mechanoreceptors: ion channels (Ca) coupled with cytoplasm proteins (on phagocytes, endothelial cells, fibroblasts), Objectives To : ❖List select mediators of Acute Inflammation ❖Describe mechanisms of action of select mediators of Acute Inflammation ❖Recognize the role of mediators in clinical expression of inflammation ❖Describe associated pathways for modulating inflammatory response