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Eric Niederhoffer SIU-SOM A 19-year-old man, lying flat on a stretcher and wearing a hard cervical collar, arrives in the Emergency Room Do you administer.

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Presentation on theme: "Eric Niederhoffer SIU-SOM A 19-year-old man, lying flat on a stretcher and wearing a hard cervical collar, arrives in the Emergency Room Do you administer."— Presentation transcript:

1 Eric Niederhoffer SIU-SOM A 19-year-old man, lying flat on a stretcher and wearing a hard cervical collar, arrives in the Emergency Room Do you administer NSAIDs or steroids to these patients? A 54-year-old woman presents to her family physician's office with a 2 week history of pain and numbness in her left hand

2 Prostaglandin, Leukotriene, Lipoxin, and Thromboxane Synthesis Pathway overview Prostaglandin receptors Pathway details Differential actions of cyclooxygenases COX-1 and COX-2 comparison Tissue comparison Role of ω-3 fatty acids

3 Linoleic acid Thromboxane A 2 synthase Lipoxygenase Arachidonic acid Prostaglandin H 2 synthase Prostaglandins (PG)Leukotrienes (LT) Thromboxanes (TXA) Anti-inflammatory steroids Glucocorticoids NSAIDs aspirin Zileuton Lipoxins (LX) Lipoxygenase Pathway Overview

4 vm/illustration/2018/a/z ReceptorSignal TransductionDistribution DP 1 (PGD 2 )AC↑, [cAMP]↑Platelets, VSM, nervous tissue, retina, small intestine, ileum, lung, stomach, uterus DP 2 (PGD 2 )Mobilize intracellular [Ca 2+ ] Eosinophils, basophils, Th2 cells EP 1 (PGE 2 )phosphoinositol turnover↑, [Ca 2+ ]↑ Kidney, lung, spleen, skeletal muscle, testis uterus EP 2 (PGE 2 )AC↑, [cAMP]↑Lung, placenta, heart? EP 3 (PGE 2 )Most receptors AC↓, [cAMP]↓, some AC↑ and [cAMP]↑ Kidney, stomach, uterus, pancreas, adrenal, testis, ovary, small intestine, brain, spleen, colon, heart, liver, skeletal muscle, lung, thymus, ileum EP 4 (PGE 2 )AC↑, [cAMP]↑Small intestine, lung, thymus, kidney, uterus, pancreas, spleen, heart, stomach, brain, ileum, peripheral blood mononuclear cells FP (PGF 2 )phosphoinositol turnover↑, [Ca 2+ ]↑ Corpus luteum, uterus, stomach, kidney, heart, lung, eye, liver IP (PGI 2 ) (IP 1, IP 2 ) [PGI 2 = prostacyclin] AC↑, [cAMP]↑Platelets, VSM, kidney, thymus, liver, lung, spleen, skeletal muscle, heart, pancreas TP (TXA 2 )phosphoinositol turnover↑, [Ca 2+ ]↑ Platelets, VSM, thymus, spleen, lung, kidney, heart, uterus Prostaglandin Receptors

5 Phospholipase A 2 (or PLC) Membrane phospholipids Cyclooxygenase O2O2 Arachidonic acid PGG 2 PGH 2 PG hydroperoxidase 2GSH GSSG NSAIDS (aspirin) Anti-inflammatory steroids Glucocorticoids (mediated by lipocortin-Ca 2+ ) IL-1R IL-1 (inflammation) PGI 2 (PC)PGE 2 PGI 2 synthasePGE 2 synthase PGD 2 PGF 2  PGD 2 synthase PGF 2 synthase PGH 2 synthase LTD 4 LTE 4 LTB 4 LTC 4 Glutathione S-transferase LTA 4 TXA 2 TXA 2 synthase PGJ 2 Pathway Details (PG, TX, LT)

6 Arachidonic acid Acyl-COX-2 Aspirin Epithelia Endothelia Monocytes 15-LOX 5-LOX 15S-H(p)ETE 15S-ETT Airway epithelia Leukocytes 15S-H(p)ETE LTA 4 12-LOX 5-LOX LTA 4 LXA 4 LXB 4 Platelets Leukocytes 15R-HETE 5-LOX 15R-ETT 15 epi-LXA 4 15 epi-LXB 4 15R-HETE Anti-Inflammatory Effects Pathway Details (LX)

7 NSAIDs COX1 Constitutive COX2 Inducible Inflammatory Endothelial integrity Vascular patency Gastric mucosal integrity Bronchodilation Renal function Platelet function Inflammation Unwanted side-effects Therapeutic anti- inflammatory effects PGE 2 PGF 2  Proteases PGI 2 PGE 2 TXA 2 Housekeeping Differential Actions of Cyclooxygenases

8 ParameterCOX-1COX-2 Regulationusually constitutive inducible Range of gene induction 2 to 4-fold10 to 80-fold Rate of gene activation 24 h0.5 to 4 h Effect of glucocorticosteroids inhibits activity* Relative size of active site smallerlarger Rate of arachidonic acid consumption 34 nmol/min/mg 39 nmol/min/mg Effect of aspirin on COX activity InhibitedAffected** COX-1 and COX-2 Comparison

9 Ar Brain/nerveVascular bedsSynovial cells PGH 2 PGF 2  PGD 2 PGE 2 PGI 2 (PC) PGE 2 PGI 2 (PC) PGE 2 TXA 2 So what would happen if we gave a patient a large dose of aspirin or Coxib to reduce inflammation/pain in these tissues? Tissue Comparison

10 Macrophage LPSTNFα TNFR TAK1 TLR4 IKKβMKK4 NFBJNK Cytokines inflammatory Nucleus Role of -3 Fatty Acids Neutrophil Platelet COX/LOX Resolvins Protectins anti-inflammatory Transcellular processes GPR120 βArr2 TAB1 DHA

11 How are prostaglandins, leukotrienes, lipoxins, and thromboxanes synthesized (substrates, enzymes, cofactors)? What is the nomenclature for prostaglandin, leukotriene, lipoxin, and thromboxane receptors? How do NSAIDs work? How do steroids work? What are important characteristics of COX-1 and COX-2? How do ω-3 fatty acids affect the inflammatory response? Review Questions


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