Senior Research Presentation - Use of CO to treat ischemia reperfusion injury


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Senior Research Presentation - Use of CO to treat ischemia reperfusion injury

  1. 1. Carbon Monoxide For Therapy?<br />The Protective Characteristics of Carbon Monoxide Used to Treat Ischemia Reperfusion Injury<br />Joshua A. Mickle<br />Advisor:<br />Prof. Jennifer Hancock<br />Tuesday, March 30th, 2010<br />
  2. 2. Background<br />Ischemia reperfusion injury (IRI)<br />Damage caused by the occlusion and subsequent return of blood supply to tissue<br /><br />
  3. 3. Why does reperfusion cause damage?<br />Combination of factors<br />Local and systemic inflammatory response<br />Leukocyte activation<br />Adherence to vessel walls <br />Transmigration to interstitial space<br />Increased edema, clotting, permeability<br />Collard & Gelman, 2001, 1134<br />
  4. 4. Why does reperfusion cause damage?<br />Reperfusion<br />Large influx of O2<br />
  5. 5. What is Carbon Monoxide (CO)?<br />Colorless, odorless, poisonous gas<br />CO greater affinity than O2 for Hemoglobin<br />Hb Unable to deliver O2<br />Disrupts cell respiration and triggers hypoxia<br /><br />
  6. 6. Why use CO for treatment?<br />CO produced naturally in body<br />Heme Oxygenase-1 system (HO-1)<br />HO-1 converts heme molecule into CO, iron, and biliverdin<br /><br />
  7. 7. Why use CO for treatment?<br />Oxidative stress shows increase in HO-1<br />Leads to increase in CO concentration in blood<br />Possibly a mechanism of protection against reactive oxygen species<br />Availability<br />Relatively well-understood toxicology<br />LOW CONCENTRATIONS<br />
  8. 8. Current Treatments for IRI<br />Ischemic preconditioning<br />Therapeutic hypothermia<br />Anti-leukocyte therapy<br />Introducing radical scavengers and antioxidants<br />Treatment of symptoms following damage<br />
  9. 9. Hypothesis<br />CO therapy is a viable option for further investigation and eventual use on humans alongside or replacing the current treatment options for IRI.<br />
  10. 10. CO Treatment Following Stroke<br />Stroke induced on rats<br />(Zeynalov E, Dore`, 2008)<br />90 min. occlusion of Middle Cerebral Artery<br />Moore & Dalley, 2006, 929<br />
  11. 11. CO Treatment<br />During reperfusion<br />subjected to various concentrations of CO<br />exposed at 0, 1, or 3 hrs following reperfusion <br />125ppm<br />At 0h<br />250ppm<br />At 0h<br />Air<br />At 0h<br />250ppm<br />At 1h<br />All for 18h of total exposure<br />250ppm<br />At 3h<br />
  12. 12. Analysis of Recovery<br />Neurological Deficit Scores (NDS)<br />Conducted at:<br />Onset of reperfusion <br />24hrs<br />48hrs<br />Scores range from 0 – 4<br />Good<br />Bad<br />
  13. 13. Results<br />
  14. 14. Also Analyzed<br />Brain tissue<br />Sliced into 2mm sections<br />Stained to show metabolic activity<br />Anterior<br />Posterior<br />
  15. 15. Also Analyzed<br />Brain Edema<br />Ipsilateral and contralateral hemispheres separated<br />% Brain Water = [(Wet – Dry)/Wet] x 100<br />
  16. 16. Not only in the Brain<br />CO treatment in rat heart transplant model<br />Akamatsu et al., 2004<br />Comparison of CO therapy during reperfusion to:<br />HO-1 activation<br />Air inhalation<br />
  17. 17. Procedures<br />Heart transplant<br />Success/failure – % survival<br />CO Exposure<br />Varying exposure to donor, graft, and/or recipient<br />400ppm<br />
  18. 18. Reagents and Results<br />
  19. 19. Results<br />Highest survival rate<br />Donor and graft exposure<br />Donor, graft, and recipient exposure<br />Interesting to note<br />Donor and Recipient exposure only<br />
  20. 20. Other studies<br />Similar results in liver and lung grafts<br />Both in vivo and ex vivo<br />(Amersi et al., 2002; Kohmoto et al., 2006)<br />Upregulation of HO-1 system<br />Increases CO endogenously<br />(Amersi et al., 1999)<br />Current goal<br />Investigate mechanisms behind these results<br />
  21. 21. Limitations to current studies<br />Small sample sizes<br />Small animal models (rats and mice)<br />Performed only on healthy specimens<br />Although better, still low survival rate<br />Need to improve before human trials<br />Long term effects<br />Dosage and duration of CO treatment<br />
  22. 22. Contradiction among studies<br />Mechanisms of action<br />Anti-inflammatory<br />Anti-apoptotic<br />Other HO-1 byproducts<br />
  23. 23. Conclusions & Implications<br />Compared to no IRI treatment:<br />CO therapy shows significantly improved tissue functioning<br />Promising for future treatments of IRI<br />Must further understand mechanism before clinical implementation<br />
  24. 24. References<br />Akamatsu Y, Haga M, Tyagi S, Yamashita K, Graca-Souza AV, Ollinger R, Czismadia E, May GA, Ifedigbo E, Otterbein LE, Bach FH, Soares MP. 2004. Heme- oxygenase-1-derived carbon monoxide protects hearts from transplant- associated ischemia reperfusion injury. The FASEB Journal. 18: 771-782.<br />Amersi F, Shen X, Anselmo D, Melinek J, Iyer S, Southard D J, Katori M, Volk H, Busuttil R W, Buelow R, Kupiec-Weglinski J W. 2002. Ex-vivo exposure to carbon monoxide prevents hepatic ischemia/reperfusion injury through p38MAP Kinase pathway. Hepatology. 35(4): 815-823.<br />Amersi F, Buelow R, Kato H, Ke B, Coito AJ, Shen X, Zhao D, Zaky J, Melinek J, Lassman CR, Kolls JK, Alam J, Ritter T, Volk HD, Farmer DG, Ghobrial RM, Busuttil RW, Kupiec-Wegelski JW. 1999. Upregulation of heme oxygenase-1 protects genetically fat Zucker rat livers from ischemia/reperfusion injury. The Journal of Clinical Investigation. 104(11): 1631-1639.<br />Kohmoto J, Nakao A, Kaizu T, Tsung A, Ikeda A, Tomiyama K, Billiar TR, Choi AMK, Murase N, McCurry KR. 2006. Low-dose carbon monoxide inhalation prevents ischemia/reperfusion injury of transplanted rat lung grafts. Surgery. 140(2): 179-185.<br />Zynalov E, Doré S. 2009. Low doses of carbon monoxide protect against experimental focal brain ischemia. Neurotoxicity Research. 15(2): 133-137.<br />
  25. 25. Acknowledgements<br />Prof. Hancock<br />Dr. Brown<br />Capstone Classmates<br />Teammates<br />
  26. 26. Questions?<br />