PT2101 AY2324 Lecture 3 Inflammation and mediators II PDF

Inflammation & Mediators II Chemotherapy and Pharmacology of Inflammation Lecture 3 R&D 9th edition, chpt 18 Dr. Orla P. Barry Dept. of Pharmacology and Therapeutics, Rm. 3.89 WGB. Email: [email protected] Mediators of Inflammation only focussing on the ones targeted by anti inflam. we want to ta...

Inflammation & Mediators II Chemotherapy and Pharmacology of Inflammation Lecture 3 R&D 9th edition, chpt 18 Dr. Orla P. Barry Dept. of Pharmacology and Therapeutics, Rm. 3.89 WGB. Email: [email protected] Mediators of Inflammation only focussing on the ones targeted by anti inflam. we want to target COX2 Arachidonic acid pathways COX1 is a good isoform that we produce at low levels needed GIT protection and normal renal blood flow 5-20% asthmatic should not USE NSAID COX2 is bad isoform upregulated Pospholipase A2 inflam causes increased arachidonic acid causes PG increase NSAID will block PG and so increase LK being produced as there is more arachidonic acid (LK CAUSE MASSIVE BRONCHOCONSTRICTION) C20 polyunsat. fatty acid Therapeutic targets for inflammation only work when bound to FLAP protein PG are a type of prostanoid Celecoxib is a PowerFUL antiinflam. Ibeprofen stops COX1+2 older NSAIDs damage GIT (can get ulcer) all asthmatic should stay away from Apirin Do not get confused with the terminology........ ➢1. Eicosanoids (autacoids) ➢2. Prostanoids (PGs, TxA2, PGI2) ➢3. Prostaglandins ➢4. Leukotrienes Eicosanoids only paracrine and autocrine... > dont want endocrine cuz it would cause inflam all over the body • The eicosanoids are considered "local hormones."  They have specific effects on target cells close to their site of formation.  They are rapidly degraded (1 minute in blood), so they are not transported to distal sites within the body.  They have roles in: Inflammation, fever, regulation of blood pressure blood clotting, immune system modulation, control of reproductive processes & tissue growth regulation of sleep/wake cycle. Eicosanoids (cont’d) chemical mediators cell damage • Mediators derived phospholipids (prostaglandins, thromboxanes, leukotrienes) • Important inflammatory mediators Arachidonic acid PGH Synthase COX1 & COX2 Lypoxygenase(s) prostaglandins thromboxanes H(P)ETEs Lts LXs Prostanoids Membrane Phospholipids Phospholipase A2 Arachidonic Acid Endoperoxide synthase: oxygenates arachidonic acid, → cyclisation to PGG2 cyclooxygenase COX 1&2 Prostaglandin G2 peroxidase Peroxidase: converts PGG2 → PGH2 Prostaglandin H2 Apisirin is better at blocking TXA2 than the other ones Specific Isomerases works better at inhibiting COX1 TXA2 platelets platelets only ave COX1 PGF2α PGE2 macrophages PGD2 mast cells PGI2 COX (cyclooxygenase) enzymes • COX-1: homeostatic functions: production of PGs for – – – – gastric cytoprotection, platelet aggregation, renal blood flow, initiation of parturition • COX-2: - constitutively expressed in the kidneys (renal medulla) – induced in inflammatory cells, by IL-1, TNF-α – Pool in the CNS (unclear) • Bifunctional enzymes; 2 distinct catalytic activities: – Dioxygenase step: 2 oxygen molecules incorporated into AA: produces highly unstable PGG2. – Peroxidase function: converts PGG2 to PGH2. PGH2 is then converted to other prostanoids by cell-specific isomerase/reductase/synthase Prostanoids prostaglandins, prostacyclin, thromboxanes Synthesized via cyclo-oxygenase at endoplasmic reticulum membrane of most cells 2 distinct activities: Endoperoxide synthase: oxygenates arachidonate, → cyclisation to PGG2 Peroxidase: converts PGG2 → PGH2 PGH2→ TXA2, thromboxane A2 (in platelets) → PGI2, prostacyclin (in endothelial cells) → PGE2, prostaglandin E2 (in macrophages) → PGD2, prostaglandin D2 (in mast cells) → PGF2α , prostaglandin F2α (uterine endothelium) Prostanoid Receptors G-protein coupled PGD2 DP DP1, DP2 PGE2 EP EP1 / EP2 / EP3 (6 isoforms) /EP4 PGF2 FP PGI2 IP TXA2 TP TPα , TP Physiological effects of prostanoids Prostanoids Tissue Physiology/effects PGE2 Many cell types (inflammatory cells) • Contraction of smooth muscles (GIT, bronchial: EP1) • Relaxation of smooth muscles (GIT, vascular and bronchial: EP2) • Gastric mucus secretion, inhibition of gastric acid secretion (EP3) • Fever • Sensitisation of peripheral sensory neurons (pain) PGI2 Vascular endothelium • Vasodilatation • Inhibition platelet aggregation • Bronchodilation PGD2 (PGJ2) Mast cells • Vasodilatation • Inhibition platelet aggregation Platelets • Vasoconstriction • Platelet aggregation • Bronchoconstriction TXA2 Prostaglandins and Inflammation PGD2, PGE2, PGI2 ❑ Production of PGs is an early event in inflammation ❑ Vasodilatation → redness,  blood flow in areas of inflammation ❑ Potentiate vessel leakiness (histamine, bradykinin) ❑ Potentiate pain sensing (bradykinin) Inhibition of synthesis produce anti-inflammatory & anti-pyretic effects by NSAIDs (Lecture 4 by Dr. A. Allshire) Leukotrienes ❑ Synthesised via cytosolic lipoxygenases in lung, platelets, mast cells, white blood cells Effects of Leukotrienes LTB 4 ❑ Initiates inflammatory response ❑ Chemotactic; adhesion & extravasation of leukocytes ❑ Promote leakiness of small blood vessels Cysteinyl leukotrienes (LTC4, D4, E4) ❑ Similar effects and have a cysteine residue in common ❑ major role in inflammatory diseases including asthma & hayfever ❑ constrict bronchial smooth muscle ❑ vasoconstriction Leukotriene Receptors CysLT1 spleen, PBLs, smooth muscle CysLT2 heart, brain, adrenal medulla, placenta CysLT1 → LTD4>LTC4>LTE4 CysLT2 → LTC4=LTD4>LTE4 Effects of Leukotrienes (cont’d) CysLT1 CysLT2 } Macrophage activation Mast cell cytokine secretion: IL-5, TNF-, IL-8 CysLT1 – Haematopoietic cytokine secretion: IL-4 Cysteinyl Leukotriene receptor antagonists CysLT1 receptor antagonists zafirlukast montelukast pranlukast } used in the treatment of asthma CysLT2 – no specific receptor antagonist presently on the market Bradykinin ➢ Vasoactive peptide ➢ Derived from a plasma α-globulin by a proteolytic enzyme cascade kallikreinkinin cascade ➢ Vasodilator: PGI2 & NO ➢ ↑ vascular permeability ➢ Pain producing agent ➢ Action potentiated by PGs Metabolism ❑Kininases I & II (kininase II is Angiotensin Converting Enzyme) ❑ACE inhibitors bring about a reduction of Ang II and an increase in BK Bradykinin Receptors ❑ Two receptors B1 & B2 ❑ B1 expressed at low levels but ↑ in inflamed tissues ❑ B1respond to Des-Arg- BK but not to bradykinin ❑ B2 receptors are constitutively expressed in normal cells and are activated by BK but not Des-Arg- BK. ❑ Although peptide antagonists have been developed none are available for clinical use BK Des-Arg-BK B2R B1R α  Gαq/11 α GDP  Endothelial cell Gαi GDP Summary Cell-derived mediators of inflammation Vascular Chemotaxis permeability Mediator Vasodilation Histamine ++ ↑↑↑ Bradikinin +++ Prostaglandins Leukotrienes Pain ↑ - +++ +++ ↑ +++ + - ↑↑↑ +++ - Cytokines Cytokine is a generic term referring to soluble factors produced by any type of cell. Lymphokine (lymphocytes) Monokine (monocytes) Chemokine (cytokine with chemotatic activity) 1. Haematopoesis 2. Inflammation 3. Immune response Autocrine Paracrine Endocrine Cytokines (cont’d) Cytokines involved in inflammation: 1. INFα and IFN 2. TNFα and TNF 3. IL-1, IL-6, IL-8 and IL-11 4. TGF2 Cytokines (cont’d) ❑ IFNs Inhibit virus replication in infected cells (e.g. treatment of Hep B and C) ❑ ILs Secreting cells for ILs: mainly mononcytes/macrophages Biological effects: neutrophil activation, chemotaxis, inflammatory mediator production induction of fever ❑ TNFs Secreting cells for TNFs: mononcytes/macrophages, neutrophils, mast cells, lymphocytes, endothelial cells and smooth muscle cells. Biological effects: increased expression of adhesion molecules, neutrophil activation, induction of fever ❑ TGF2 Secreting cells for TGF2: platelets and osteoclasts mainly but also mononcytes/macrophages and neutrophils Biological effects: enhancement in integrin expression and increased chemotaxis of monocytes and neutrophils Local cytokine effects Macrophage 1. TNFα IL-1 Endothelium + + + TNFα IL-1 Fibroblast 2. Macrophage -TGF2 TGF2 Endothelium + + Fibroblast Systemic cytokine effects 1. Macrophage TNFα IL-1 IL-6 Acute phase proteins (anti-inflammatory) Macrophage TNFα IL-1 IL-6 PGE 2. FEVER Systemic cytokine effects (cont’d) TNFα IL-1 IL-6 3. Macrophage + Acute phase proteins (anti-inflammatory) - Glucocorticoids ACTH Complement Set of serine esterase/protease enzymes Exist under natural conditions as zymogens Two pathways of possible activation 1. Classical 2. Alternate C3a, C4a and C5a are potent mediators of inflammation Release of histamine from mast cells and basophils Smooth muscle contraction Increased vascular permeability C3a, C4a and C5a are called anaphylatoxins for their ability to induce ANAPHYLAXIS New look at inflammation By Christine Gorman & Alice Park Time Magazine, Feb. 23, 2004 Inflammation & Inflammatory Disease Asthma CAD Cancer Alzheimer’s disease Diabetes