Transcript pptx
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 A 19-year-old man, lying flat on a stretcher and wearing a hard cervical collar, arrives in the Emergency Room Do you administer nonsteroidal anti-inflammatory drugs or steroids to these patients? Eric Niederhoffer Medical Biochemistry Prostaglandin, Leukotriene, Lipoxin, and Thromboxane Synthesis •Pathway overview •Prostaglandin receptors •Pathway details (transcellular) •Differential actions of cyclooxygenases •COX-1 and COX-2 comparison •Tissue comparison •Role of ω-3 fatty acids Pathway Overview Leukotriene receptor antagonists (zafirlukast, montelukast) Anti-inflammatory steroids Glucocorticoids NSAIDs aspirin Linoleic acid Zileuton Arachidonic acid Prostaglandin H2 synthase Lipoxygenase “Transcellular” Prostaglandins (PG) Leukotrienes (LT) Thromboxane A2 synthase Lipoxygenase Lipoxins (LX) Thromboxanes (TXA) Prostaglandin Receptors Receptor Signal Transduction Distribution DP1 (PGD2) AC↑, [cAMP]↑ Platelets, VSM, nervous tissue, retina, small intestine, ileum, lung, stomach, uterus DP2 (PGD2) Mobilize intracellular [Ca2+] Eosinophils, basophils, Th2 cells EP1 (PGE2) phosphoinositol turnover↑, [Ca2+]↑ Kidney, lung, spleen, skeletal muscle, testis uterus EP2 (PGE2) AC↑, [cAMP]↑ Lung, placenta, heart? EP3 (PGE2) 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 EP4 (PGE2) AC↑, [cAMP]↑ Small intestine, lung, thymus, kidney, uterus, pancreas, spleen, heart, stomach, brain, ileum, peripheral blood mononuclear cells FP (PGF2) phosphoinositol turnover↑, [Ca2+]↑ Corpus luteum, uterus, stomach, kidney, heart, lung, eye, liver IP (PGI2) (IP1, IP2) AC↑, [cAMP]↑ Platelets, VSM, kidney, thymus, liver, lung, spleen, skeletal muscle, heart, pancreas phosphoinositol turnover↑, [Ca2+]↑ Platelets, VSM, thymus, spleen, lung, kidney, heart, uterus [PGI2 = prostacyclin] TP (TXA2) http://www.caymanchem.com/app/template/scientificIllustrations %2CIllustration.vm/illustration/2018/a/z Pathway Details (PG, TX, LT) IL-1/BDK (inflammation) IL-1R BDKR Gi/Gq Membrane phospholipids Phospholipase A2 (or PLC) Anti-inflammatory steroids Glucocorticoids (mediated by lipocortin-Ca2+) Arachidonic acid NSAIDS (aspirin) LTA4 LTA hydrolase Cyclooxygenase Glutathione S-transferase O2 LTB4 LTC4 PGH2 synthase PGG2 2GSH LTD4 PG hydroperoxidase GSSG LTE4 PGJ2 PGD2 synthase TXA2 synthase PGH2 PGD2 TXA2 PGI2 synthase PGI2 (PC) PGE2 synthase PGF2 synthase PGF2a PGE2 Transcellular Pathway Details (LX) Arachidonic acid Epithelia Endothelia Monocytes Aspirin Airway epithelia Acyl-COX-2 Leukocytes 15-lipoxygenase 5-lipoxygenase 15S-H(p)ETE 15R-HETE LTA4 Leukocytes Platelets 15R-HETE 15S-H(p)ETE LTA4 5-lipoxygenase 5-lipoxygenase 15R-epoxytetraene 15S-epoxytetraene 15 epi-LXA4 15 epi-LXB4 12-lipoxygenase + hydrolases LXA4 Anti-Inflammatory Effects http://themedicalbiochemistrypage.org/aspirin.html# LXB4 Differential Actions of Cyclooxygenases Housekeeping Unwanted side-effects PGI2 Endothelial integrity Vascular patency Gastric mucosal integrity PGE2 Bronchodilation Renal function TXA2 Platelet function COX1 Constitutive NSAIDs Generally Inducible Inflammatory COX2 PGE2 PGF2a Proteases Therapeutic antiinflammatory effects Inflammation COX-1 and COX-2 Comparison Parameter COX-1 COX-2 Regulation usually constitutive generally inducible Range of gene induction 2 to 4-fold 10 to 80-fold Rate of gene activation 24 h 0.5 to 4 h Effect of glucocorticosteroids decreases activity* decreases activity* Relative size of active site smaller larger Rate of arachidonic acid consumption 34 nmol/min/mg 39 nmol/min/mg Effect of aspirin on COX activity Inhibited Affected** http://elfstrom.com/arthritis/nsaids/actions.html Tissue Comparison Brain/nerve Synovial cells Vascular beds Ar Ar Ar PGH2 PGH2 PGH2 PGD2 PGE2 PGF2a PGI2 (PC) PGE2 PGI2 (PC) PGE2 TXA2 So what would happen if we gave a patient a large dose of aspirin or Coxib to reduce inflammation/pain in these tissues? Role of 𝛚-3 Fatty Acids DHA LPS TNFα TNFR Neutrophil COX/LOX GPR120 βArr2 TAB1 TLR4 Transcellular processes Platelet TAK1 IKKβ NF𝛋B COX/LOX MKK4 JNK Resolvins Protectins anti-inflammatory Nucleus Cytokines inflammatory Macrophage Review Questions • 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?