PT2101 AY2324 Lecture 2 Inflammation and mediators I Dr. Órla P. Barry.pdf

Inflammation & Mediators 1 Chemotherapy and Pharmacology of Inflammation Lecture 2 R&D 9th edition, chpts 7, 18 Dr. Órla P. Barry Dept. of Pharmacology and Therapeutics, Rm. 3.89 WGB. Email: [email protected] What do you know already regarding inflammation? Triggers of Inflammation CARDIANL signs...

Inflammation & Mediators 1 Chemotherapy and Pharmacology of Inflammation Lecture 2 R&D 9th edition, chpts 7, 18 Dr. Órla P. Barry Dept. of Pharmacology and Therapeutics, Rm. 3.89 WGB. Email: [email protected] What do you know already regarding inflammation? Triggers of Inflammation CARDIANL signs • provoked response to tissue injury • • • • chemical agents cold, heat trauma invasion of microbes acute inflam. =>resolves problems and short • serves to destroy, dilute or wall off the injurious agent • induces repair • protective response • can be potentially harmful weeks months or years chronic inflam. is persistant and harmful Acute vs Chronic Inflammation • Acute (short-term) inflammation is beneficial • Chronic (long-term) inflammation is a major problem and plays a major role in almost every chronic Western disease • • • • • Cancer Heart disease Metabolic syndrome Alzheimer’s disease Various degenerative conditions • Anything that can help fight chronic inflammation is of potential importance in preventing and even treating these diseases Examples of Inflammatory Diseases Overall incidence : 25% Major pathologies: Steps of Inflammation 1. acute inflammation 2. immune response 3. chronic inflammation Five Cardinal Signs of Inflammation Acute Inflammation Pain => Bradykinin ACUTE INFLAMMATION Response to infection/ noxious substance/ tissue damage. Innate (and specific immune) response. 1. 2. 3. 4. Release of chemical mediators. Vasodilatation and increased blood flow. Exudation of plasma and blood cells ► oedema and swelling. Further release mediators ►attract inflammatory cells (neutrophils, monocytes). mediators are produced by the endothelial cells neutrophils are first to be attracted to an event Acute Inflammation (cont’d) Acute inflammation involves: ✓alteration of vascular caliber following very brief vasoconstriction (seconds), vasodilation leads to increased blood flow and blood pooling creating redness and warmth (rubor and calor) ✓changes of microvasculature increased permeability for plasma proteins and cells creating swelling (tumor). Fluid loss leads to concentration of red blood cells and slowed blood flow (stasis) ✓emigration of leukocytes from microcirculation due to stasis and activation leads migration towards offending agent Inflammation step by step 1. 2. 3. 4. 5. 6. pathogen/cell injury release of mediators vasodilitation exudation of plasma oedema and swelling attraction of neutrophils Acute inflammation: Resolution cancer -> constant vasodilation primary tumour is not a fatal but secondary metastasis is a major issue and a poor prognosis neutrophils are no present in chronic inflammation they are only around the first 24hrs-48hrs (just to phagocytose) Trigger Cell Mechanism response minutes X Resolution hours days/weeks Non resolved chronic inflammation Chronic Inflammation methotrexate is for rheumatoid arthritis e.g. rheumatoid arthritis: pain, destruction of bone and cartilage • inflammation without resolution of the injury • tissue damage and repair (scar formation, fibroblast infiltration) • involves ‘specific’ mediators ibuprofen is to reduce amount of prostaglandins ALL PRO INFLAMMATORY CYTOKINES Mediator Sources Primary effects Interleukin 1,2,3 Macrophages, T-lymphocytes Lymphocyte activation Prostaglandin production TNF-α Macrophages Prostaglandin production Interferons Macrophages, T-lymphocytes Endothelial cells many Platelet derived Growth factor Macrophages, fibroblasts, Endothelial cells, platelets Fibroblasts, proliferation maxrophages are always present in chronic inflam. Chronic Inflammation step by step 1. chronic inflammation a. immune cells b. mediators 2. cell/tissue damage 3. repair a. scar formation b. fibrosis Summary of Acute vs Chronic Inflammation Acute Etiology Duration Brief & Intense Days Nature Exudative Consequence Resolution Chronic Persistent & Indolent Weeks to months Proliferative Fibrous scarring Cells of Inflammation Acute inflammation Chronic inflammation Neutrophils Eosinophils Basophils Endothelial cells Macrophages Macrophages Lymphocytes Plasma cells Endothelial cells Fibroblasts Chemical Mediators of Inflammation Cell derived products 1. Vasoactive amines (histamine, serotonin) 2. Cytokines and growth factors 3. AA (arachidonic acid) derivatives 4. PAF (platelet activating factor) 5. Lysosomal enzymes 6. ROS (reactive oxygen species) 7. NO (nitric oxide) histamine and arachadonic acids Plasma derived products 1. 2. 3. 4. The kinin system (bradykinin) Coagulation system Fibrinolytic system Complement system these will be covered in other lectures Cells of Inflammation Neutrophils compliment cascade Short lived cells Chemoattractants: IL-8, C3a, C5a, lipid mediators C3a activates basophils cells glycogen multilobed nucleus secondary granule Phagocytosis mostly opsonization with Fc receptors Mediators released from Neutrophils: Oxygen radicals Enzymes; proteases, PLs, collagenases Lysozyme splits the peptidogycan cell wall of bacteria need to be attarcted to the damaged area Primary Azurophilic granule Basophils and Mast cells ibuprofen (doesn't stop leukotrienes only stops prostagladins) • Responsible for inflammatory and anaphylactic responses • Secrete – Histamine, Leukotrienes, Prostaglandins • Activated by binding with IgE antigen Y Y IgEY mast cells make: histamine histamine prostaglandins leukotrienes vasodilitation bronchoconstriction oedema Macrophages phagosome pseudopodia Activted by Ag or cytokines Phagocytosis or opsonization Factors secreted by activated macrophages Factor IL-1 phagolysosome Function promote inflammatory responses & fever Lysosome IL-6 & TNFα promote innate immunity & elimination of pathogens Hydrolytic enzymes promote inflammatory response IFNα protects cells against viral infection T Lymphocytes T lymphocytes • Express T cell receptor (TCR) • Interact with antigen-presenting cells through MHC receptor • T helper cells (Th;CD4+) for B cell and cytotoxic T cells (Tc; CD8+) T Target cell T c T c Th T c antigen-presenting cells: dendritic cells, macrophages APC Tm B Lymphocytes B Y YYY B lymphocytes • antibody production: different immunoglobulin (Ig) classes • Immunoglobulins types: – IgG PC – IgM – IgA – IgE (immediate hypersensitivity binds to basophils and mast cells) Th • are activated by Th cells Target cell Bm PC B APC Mediators of Inflammation Histamine CO2 Histidine Location Histamine Histidine decarboxylase N CH2 CH2 N NH2 Mast cells and basophils Lungs, skin, GI tract Histaminocytes (stomach) Histaminergic neurones (brain) Release 1. Activated by binding with IgE Y Y Y histamine in gym (skin cells) Histamine is preformed and stored While PG and LK are made when needed histamine vasodilitation bronchoconstriction oedema General History of Antihistamines Histamine discovered 1910 First antihistamines (AHs) synthesized 1937 Antihistamines introduced for clinical use 1942 First CNS effects of AHs reported 1943 Antiallergic effects of AHs described 1955 2nd generation AHs introduced 1981 Cardiotoxic effects of AHs reported 1986 Human H2 receptor cloned 1991 Human H1 receptor cloned 1993 H1 receptor polymorphism described 1998 Modified from Simons FER. Antihistamines, Chapter 51, in Middleton's Allergy: Principles and Practice, Mosby, 6th Edition, 2003 1999 2000 Human H3 receptor cloned Human H4 receptor cloned Histamine Receptors: Distribution and Function just know H1 ✓ H1 - Smooth muscle, endothelium, CNS. Vasodilation, bronchoconstriction, separation of endothelial cells, pain and itching, allergic rhinitis, motion sickness. ✓ H2 - Parietal cell, vascular smooth muscle cell. Stimulates gastric acid secretion, vasodilation (in peptic ulcers). Can also increase cardiac rate and output. ✓ H3 - CNS cells, and some in peripheral NS. Presynaptic, feedback inhibition of histamine synthesis and release. They also control release of DA, GABA, ACh, 5-HT and NE ✓ H4 - Highly expressed in bone morrow and white blood cells. Mediate mast cell chemotaxis. H1 Receptor Histamine PIP3 DAG PLC GDP α   P Gαq/11 GTP P P PKC α P P PKC P IP3 Ca2+ IP3R Ca2+-calmodulin-dependent protein kinases Gαq-protein activation leads to PLC-catalysed hydrolysis of membrane inositide phospholipids and initiation of IP3 cascade; protein kinase C activation & Ca+2 mobilisation; inducing nitric oxide & cellular response Activation of trc factor NF-kB. drives the transcription of genes involved in inflammation Antagonists of Histamine receptors more like Inverse Agonist Antagonists Receptor subtype H1 10 generation can be promethazine, diphenhydramine, mepyramine 20 generation withdrawn from market due to cardiotoxicity astemizole, terfenadine cetirizine, loratidine cant pass thru BBB 30 generation fexofenadine, desloratadine, carebastine H2 10 generation cimetidine 20 generation ranitidine, famotidine, zolantidine H3 thioperimide, ciproxifan, clobenpropit H4 thioperimide passing thru the BBB (sedating) stops histamine binding Clinical uses of antihistamines 1.Allergic rhinitis 2.Allergic conjunctivitis 3.Contact dermatitis 4.Urticaria 5.Pruritis 6.Anaphylactic shock (adjunct only) Commonly used H1 antihistamines ✓ promethazine (Phenergan) sedating ✓diphenhydramine (Benadryl) sedating ✓ triprolidine (Sudafed) non-sedating ✓ fexofenadine (Allegra) non-sedating ✓loratidine (Claritin) non-sedating ✓desloratadine (Clarinex) non-sedating ✓certirize (Zyrtec) non-sedating Benefits of H1 Antihistamines H1 receptor NF-B Ca2+ Decreased allergic inflammation, itching, sneezing, rhinorrhea, and whealing ion channels Decreased Ag presentation, expression of cell-adhesion molecules, chemotaxis, and proinflammatory cytokines Decreased mediator release Potential adverse effects of H1 antihistamines NOT SPECFIC so they work on other receptors H1 receptor Decreased neurotransmission in the CNS, increased sedation, decreased cognitive and psychomotor performance, and increased appetite Muscarinic receptor Increased dry mouth, urinary retention, and sinus tachycardia α-Adrenergic receptor Hypotension, dizziness, and reflex tachycardia Serotonin receptor Increased appetite Cardiac Ion channels Prolonged QT anti intervals, depressants sometimes cause u to resulting increase in weight ventricular arrhythmias 1st vs 2nd generation H1 antihistamines First-generation H1 antihistamines ❑Usually administered in three to four daily doses ❑Cross the blood-brain barrier (lipophilicity, low molecular weight, lack of recognition by the P-glycoprotein efflux pump) ❑Potentially cause side-effects (sedation/hyperactivity/insomnia/convulsions) ❑Case reports of toxicity are regularly published ❑No randomized, double-blind, placebo-controlled studies in children ❑Lethal dose identified for infants/young children Second-generation H1 antihistamines ❑Usually administered once or twice a day ❑Do not cross the blood-brain barrier (lipophobicity, high molecular weight, recognition by the P-glycoprotein efflux pump) ❑Do not cause relevant side-effects (sedation/fatigue/hyperactivity/convulsions) in the absence of drug interactions ❑No reports of serious toxicity ❑Some randomized, double-blind, placebo-controlled studies in children ❑Do not cause fatality in overdose