Attribution: University of Michigan Medical School, Department of Microbiology andImmunologyLicense: Unless otherwise note...
Citation Key                                    for more information see: http://open.umich.edu/wiki/CitationPolicyUse + S...
Arachadonic Acid Metabolism              M1 – Immunology Sequence                 Joseph Fantone, MDWinter 2009
How many take aspirin, ibuprofen,      tylenol, naproxen ?           Why???
INFLAMMATORY MEDIATORSPLASMA DERIVED                     CELL-DERIVED• COMPLEMENT CASCADE                • VASOACTIVE AMIN...
Intended Learning Outcomes          To Understand The:•  Primary inflammatory mediators derived from the   metabolism of a...
What is Arachidonic Acid?                              COOHJ. Fantone
How And Where Is Arachidonic Acid Generated?            chocolateBear (Wikispaces)
Lipid Mediators of Inflammation                                    Cell membrane   Stimulus                               ...
Source Undetermined
What are the primary products derived from arachidonic acid?•  Cyclooxygenase (COX)•  Lipoxygenase (LO)
Acute inflammation: lipid mediators                                  Cell membraneStimulus                                ...
Source Undetermined
CELL SPECIFICITY OF ARACHIDONIC    ACID-DERIVED PRODUCTSCELL                  PRODUCTNeutrophils            LeukotrienesMa...
In Vivo Effects of Arachidonic Acid       Derived Products: Regulates• Thermostatic Set Point (Fever)• Pain (Interacts wit...
Biological Function of Arachidonic                Acid ProductsCyclooxygenase-derived Products:Prostaglandin E2/Prostacycl...
The HomeostaticBalance                                                                                            Endothel...
Production of Fever                   Hypothalamus Thermoregulatory Area                                        COX inhibi...
Biological FunctionLipoxygenase-derived Products:Leukotriene B4          Neutrophil Activation                            ...
Pharmacologic Regulation of Arachidonic
        Acid-Derived Products: Modulate        •  Phospholipase activity:     –  S...
Non- Steroidal Anti-Inflammatory          Compounds; NSAIDS    •     Aspirin (acetysalicylic acid)•     Ibuprofen (propioni...
COX-2 Inhibitors• CELEBREX (Celecoxib) Pfizer-(Pharmacia)• BEXTRA (Valdecoxib) Pfizer• VIOXX (Rofecoxib) Merck     Osteoarth...
Aspirin• Irreversible inhibition of cyclooxygenase• Acetylates active site of enzyme• Decreased production of products (e....
Source UndeterminedNSAIDS: Inhibit cyclooxygenase: reversible binding            to active site of enzyme
AN ASPIRIN A DAY Regents of the University of Michigan
Regents of the University of Michigan
Aspirin Anti-thrombogenic Activity• Inhibitsplatelet aggregation; blocks platelet-derivedthromoboxane production• Blocks p...
Acute inflammation: lipid mediators               An important role in vascular homeostasis             Endothelium       ...
Acute inflammation: lipid mediators                                          Therapeutic targets                     Endot...
Acute inflammation: lipid mediators                                  Therapeutic targets              Endothelium         ...
Acute inflammation: lipid mediators                                    Therapeutic targets                Endothelium     ...
COX-2 inhibitors work by blocking COX-2 enzyme which is     involved ingastrointestinal toxicity is reduced       the infl...
Acute inflammation: lipid mediators                                     Therapeutic targets               Endothelium     ...
Fish Oil: Protective EffectsEicosapentanoic Acid            Arachidonic Acid                      Omega-3   Omega-6     So...
Acute inflammation: lipid mediators                                     Cell membraneStimulus                             ...
Thank You
Additional Source Information                           for more information see: http://open.umich.edu/wiki/CitationPolic...
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02.10.09(c): Arachadonic Acid Metabolism

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02.10.09(c): Arachadonic Acid Metabolism

  1. 1. Attribution: University of Michigan Medical School, Department of Microbiology andImmunologyLicense: Unless otherwise noted, this material is made available under the terms ofthe Creative Commons Attribution–Noncommercial–Share Alike 3.0 License:http://creativecommons.org/licenses/by-nc-sa/3.0/ We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability touse, share, and adapt it. The citation key on the following slide provides information about how you may share and adaptthis material.Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions,corrections, or clarification regarding the use of content.For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or areplacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to yourphysician if you have questions about your medical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
  2. 2. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Adapt { Content the copyright holder, author, or law permits you to use, share and adapt. } Public Domain – Government: Works that are produced by the U.S. Government. (USC 17 § 105) Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Creative Commons – Zero Waiver Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation LicenseMake Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (USC 17 § 102(b)) *laws in your jurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. } Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (USC 17 § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
  3. 3. Arachadonic Acid Metabolism M1 – Immunology Sequence Joseph Fantone, MDWinter 2009
  4. 4. How many take aspirin, ibuprofen, tylenol, naproxen ? Why???
  5. 5. INFLAMMATORY MEDIATORSPLASMA DERIVED CELL-DERIVED• COMPLEMENT CASCADE • VASOACTIVE AMINES C3a, C5a histamine, serotonin• COAGULATION CASCADE • OXYGEN METABOLITES Thrombin, plasmin hydrogen peroxide (H202) superoxide anion (02-) hypochlorous acid (HOCl-) • ARACHIDONIC ACID METABOLITES cyclooxygenase-derived lipoxygenase-derived • CYTOKINES Interleukins Chemokines Interferons Growth Factors Tumor Necrosis Factor
  6. 6. Intended Learning Outcomes To Understand The:•  Primary inflammatory mediators derived from the metabolism of arachidonic acid including their primary cellular source and biological activity.•  Effects of nonsteroidal anti-inflammatory compounds on blocking the production of arachidonic acid metabolites during disease•  Mechanism of aspirin therapy and diets rich in fish containing high levels of omega 3 fatty acids as potentially important in lowering the incidence of cardiovascular disease.
  7. 7. What is Arachidonic Acid? COOHJ. Fantone
  8. 8. How And Where Is Arachidonic Acid Generated? chocolateBear (Wikispaces)
  9. 9. Lipid Mediators of Inflammation Cell membrane Stimulus Phospholipids + Phospholipase Arachidonic acidJ. Fantone
  10. 10. Source Undetermined
  11. 11. What are the primary products derived from arachidonic acid?•  Cyclooxygenase (COX)•  Lipoxygenase (LO)
  12. 12. Acute inflammation: lipid mediators Cell membraneStimulus Phospholipids + Phospholipase Arachidonic acid COX-1+2 COX-1 Lipooxygenases (5-LO) Prostaglandins Thromboxanes Leukotrienes Prostaglandin E2 LTB4 Prostacyclin PGI2 TXB2 LTC4, LTD4 J. Fantone
  13. 13. Source Undetermined
  14. 14. CELL SPECIFICITY OF ARACHIDONIC ACID-DERIVED PRODUCTSCELL PRODUCTNeutrophils LeukotrienesMacrophage/Monocyte Prostaglandins + LeukotrienesPlatelets ThromboxaneEndothelial Cells Prostacyclin
  15. 15. In Vivo Effects of Arachidonic Acid Derived Products: Regulates• Thermostatic Set Point (Fever)• Pain (Interacts with pain receptors)• Blood Flow• Leukocyte Activity•  Platelet Function
  16. 16. Biological Function of Arachidonic Acid ProductsCyclooxygenase-derived Products:Prostaglandin E2/Prostacyclin Immunoregulatory •Inhibits Immune cell activation •Inhibits cytokine production •Inhibits mast cell activation Blocks platelet aggregation Increases vasodilation Thromboxane Causes vasoconstriction Induces platelet aggregation
  17. 17. The HomeostaticBalance        Endothelium  Platelets  PGI2  TXA2  Regents of the University of Michigan
  18. 18. Production of Fever Hypothalamus Thermoregulatory Area COX inhibitors (aspirin)Endogenous pyrogens (Interleukins -1,-6) Arachidonic acid X ProstaglandinsExogenous pyrogens (bacterial products) Increase temp set-point J. Fantone
  19. 19. Biological FunctionLipoxygenase-derived Products:Leukotriene B4 Neutrophil Activation - chemotaxis - degranulation Mast cell activation - degranulationLeukotriene C,D,E Smooth muscle contraction(SRS-A) Increase vascular permeability
  20. 20. Pharmacologic Regulation of Arachidonic
 Acid-Derived Products: Modulate •  Phospholipase activity: –  Suppress the release of arachidonic acid (no substrate available) –  Blocks both COX and LO-derived products•  Cyclooxygenase Activity: –  Blocks Cyclooxygenase-derived products –  COX-1 and COX-2 inhibitors•  Specific enzymes down-stream from COX: –  Thromboxane synthetase inhibitors•  Lipoxygenase activity: –  Block 5-lipoxygenase enzyme –  Small molecule receptor antagonists for cysteinyl leukotrienes
  21. 21. Non- Steroidal Anti-Inflammatory Compounds; NSAIDS •  Aspirin (acetysalicylic acid)•  Ibuprofen (propionic acid derivatives)•  Indomethacin (indole derivatives)•  Tylenol (acetominophen)•  COX-2 Inhibitors (Vioxx, celebrex, Bextra)
  22. 22. COX-2 Inhibitors• CELEBREX (Celecoxib) Pfizer-(Pharmacia)• BEXTRA (Valdecoxib) Pfizer• VIOXX (Rofecoxib) Merck Osteoarthritis Rheumatoid arthritis Primary dysmenorrhea Pain management
  23. 23. Aspirin• Irreversible inhibition of cyclooxygenase• Acetylates active site of enzyme• Decreased production of products (e.g.prostaglandins, prostacylcins & thromboxanes) Source Undetermined
  24. 24. Source UndeterminedNSAIDS: Inhibit cyclooxygenase: reversible binding to active site of enzyme
  25. 25. AN ASPIRIN A DAY Regents of the University of Michigan
  26. 26. Regents of the University of Michigan
  27. 27. Aspirin Anti-thrombogenic Activity• Inhibitsplatelet aggregation; blocks platelet-derivedthromoboxane production• Blocks platelet cyclooxygenase for the life of the platelet; nonew protein synthesis• Blocks endothelial cell-derived prostacyclin• Suppression of endothelial cell-derived prostacyclin is shortlived as endothelial cells can generation new cyclooxygenaseenzyme• Platelet activity is blocked more than endothelial cell activity
  28. 28. Acute inflammation: lipid mediators An important role in vascular homeostasis Endothelium Platelets Prostacyclin PGI2 TXB2 Anti-thrombotic Pro-thromboticJ. Fantone
  29. 29. Acute inflammation: lipid mediators Therapeutic targets Endothelium PlateletsAspirin All cells but the platelet Aspirin X can resynthesize theinhibits COX-2 irreversibly enzymes X inhibits COX-1 irreversibly Prostacyclin PGI2 TXB2 tic thro mbo Pro- botic t hrom J. Fantone Anti-
  30. 30. Acute inflammation: lipid mediators Therapeutic targets Endothelium Platelets COX-2 COX-1 Prostacyclin PGI2 TXB2 Anti-thrombotic Pro-thrombotic NSAIDs inhibit both COX-1 and COX-2; COXIBs inhibit COX-2J. Fantone
  31. 31. Acute inflammation: lipid mediators Therapeutic targets Endothelium Platelets COX-2 X Ibuprofen* X COX-1 Prostacyclin PGI2 TXB2 Anti-thrombotic Pro-thrombotic* Classical NSAID, it inhibits both COX enzymes J. Fantone
  32. 32. COX-2 inhibitors work by blocking COX-2 enzyme which is involved ingastrointestinal toxicity is reduced the inflammation pathway. By sparing COX-1 Source Undetermined
  33. 33. Acute inflammation: lipid mediators Therapeutic targets Endothelium Platelets COX-2 X Vioxx® COX-1 Prostacyclin PGI2 TXB2 Anti-t hrom botic Pro-t hrom boticJ. Fantone
  34. 34. Fish Oil: Protective EffectsEicosapentanoic Acid Arachidonic Acid Omega-3 Omega-6 Source Undetermined Source Undetermined
  35. 35. Acute inflammation: lipid mediators Cell membraneStimulus Phospholipids + Phospholipase Arachidonic acid COX-1+2 COX-1 Lipooxigenases (5-LO) Prostaglandins Thromboxanes Leukotrienes Prostaglandin E2 LTB4 Prostacyclin PGI2 TXB2 LTC4, LTD4 Vasodilation . Increase vascular permeability. Control platelet aggregation . Chemotaxis . Pain . Fever J. Fantone
  36. 36. Thank You
  37. 37. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 7: J. FantoneSlide 8: chocolateBear, Wikispaces, https://illnessesanimalsplants.wikispaces.com/Selectively%20Permeable%20Lipid%20BilayerSlide 9: J. FantoneSlide 10: Source UndeterminedSlide 12: J. FantoneSlide 13: Source UndeterminedSlide 17: Regents of the University of MichiganSlide 18: J. FantoneSlide 23: Source UndeterminedSlide 24: Source UndeterminedSlide 25: Regents of the University of MichiganSlide 26: Regents of the University of MichiganSlide 28: J. FantoneSlide 29: J. FantoneSlide 30: J. FantoneSlide 31: J. FantoneSlide 32: Source UndeterminedSlide 33: J. FantoneSlide 34: Source Undetermined; Source UndeterminedSlide 35: J. Fantone

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