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Eric Niederhoffer SIU-SOM

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 NSAIDs or steroids to these patients?.

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Eric Niederhoffer SIU-SOM

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  1. 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 NSAIDs or steroids to these patients? Eric Niederhoffer SIU-SOM

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

  3. Anti-inflammatory steroids Glucocorticoids Benoxaprofen Zileuton NSAIDs aspirin Arachidonic acid Prostaglandins (PG) Leukotrienes (LT) Lipoxygenase Lipoxins (LX) Thromboxanes (TXA) Dazoxiben Pathway Overview Linoleic acid Lipoxygenase Prostaglandin H2 synthase Thromboxane A2 synthase

  4. Prostaglandin Receptors http://www.caymanchem.com/app/template/scientificIllustrations%2CIllustration.vm/illustration/2018/a/z

  5. IL-1 (inflammation) IL-1R Anti-inflammatory steroids Glucocorticoids (mediated by lipocortin-Ca2+) Arachidonic acid LTA4 NSAIDS (aspirin) Glutathione S-transferase PGG2 LTB4 LTC4 2GSH PGH2 synthase LTD4 GSSG PGH2 LTE4 PGJ2 TXA2 synthase PGD2 TXA2 PGI2 (PC) PGE2 PGF2a Pathway Details (PG, TX, LT) Membrane phospholipids Phospholipase A2 (or PLC) O2 Cyclooxygenase PG hydroperoxidase PGD2 synthase PGI2 synthase PGE2 synthase PGF2 synthase

  6. Epithelia Endothelia Monocytes Aspirin Airway epithelia Leukocytes Acyl-COX-2 15-LOX 5-LOX 15S-H(p)ETE 15R-HETE LTA4 Leukocytes Platelets 15R-HETE 15S-H(p)ETE LTA4 5-LOX 5-LOX 15R-ETT 15S-ETT 12-LOX LXA4 LXB4 15 epi-LXA4 15 epi-LXB4 Pathway Details (LX) Arachidonic acid Anti-Inflammatory Effects http://themedicalbiochemistrypage.org/aspirin.html#

  7. Unwanted side-effects PGI2 COX1 Constitutive PGE2 TXA2 PGE2 PGF2a Inducible Inflammatory COX2 Proteases Therapeutic anti-inflammatory effects Differential Actions of Cyclooxygenases Housekeeping Endothelial integrity Vascular patency Gastric mucosal integrity Bronchodilation Renal function Platelet function NSAIDs Inflammation

  8. COX-1 and COX-2 Comparison http://elfstrom.com/arthritis/nsaids/actions.html

  9. Brain/nerve Synovial cells Vascular beds Ar Ar Ar PGH2 PGH2 PGH2 PGD2 PGE2 PGI2 (PC) PGE2 PGI2 (PC) PGE2 PGF2a TXA2 Tissue Comparison So what would happen if we gave a patient a large dose of aspirin or Coxib to reduce inflammation/pain in these tissues?

  10. Role of 𝛚-3 Fatty Acids DHA Neutrophil LPS TNFα COX/LOX GPR120 TNFR Transcellular processes βArr2 TLR4 TAB1 Platelet TAK1 COX/LOX IKKβ MKK4 Resolvins Protectins anti-inflammatory NF𝛋B JNK Cytokines inflammatory Nucleus Macrophage

  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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