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

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  • 1. Carbon Monoxide For Therapy?
    The Protective Characteristics of Carbon Monoxide Used to Treat Ischemia Reperfusion Injury
    Joshua A. Mickle
    Advisor:
    Prof. Jennifer Hancock
    Tuesday, March 30th, 2010
  • 2. Background
    Ischemia reperfusion injury (IRI)
    Damage caused by the occlusion and subsequent return of blood supply to tissue
    http://hyperbaricworx.com.au/images/How2.png
  • 3. Why does reperfusion cause damage?
    Combination of factors
    Local and systemic inflammatory response
    Leukocyte activation
    Adherence to vessel walls
    Transmigration to interstitial space
    Increased edema, clotting, permeability
    Collard & Gelman, 2001, 1134
  • 4. Why does reperfusion cause damage?
    Reperfusion
    Large influx of O2
  • 5. What is Carbon Monoxide (CO)?
    Colorless, odorless, poisonous gas
    CO greater affinity than O2 for Hemoglobin
    Hb Unable to deliver O2
    Disrupts cell respiration and triggers hypoxia
    http://www.jems.com/Images/CO_Fig1_tcm16-186547.jpg
  • 6. Why use CO for treatment?
    CO produced naturally in body
    Heme Oxygenase-1 system (HO-1)
    HO-1 converts heme molecule into CO, iron, and biliverdin
    http://www.bioscience.org/2007/v12/af/2130/figures.htm
  • 7. Why use CO for treatment?
    Oxidative stress shows increase in HO-1
    Leads to increase in CO concentration in blood
    Possibly a mechanism of protection against reactive oxygen species
    Availability
    Relatively well-understood toxicology
    LOW CONCENTRATIONS
  • 8. Current Treatments for IRI
    Ischemic preconditioning
    Therapeutic hypothermia
    Anti-leukocyte therapy
    Introducing radical scavengers and antioxidants
    Treatment of symptoms following damage
  • 9. Hypothesis
    CO therapy is a viable option for further investigation and eventual use on humans alongside or replacing the current treatment options for IRI.
  • 10. CO Treatment Following Stroke
    Stroke induced on rats
    (Zeynalov E, Dore`, 2008)
    90 min. occlusion of Middle Cerebral Artery
    Moore & Dalley, 2006, 929
  • 11. CO Treatment
    During reperfusion
    subjected to various concentrations of CO
    exposed at 0, 1, or 3 hrs following reperfusion
    125ppm
    At 0h
    250ppm
    At 0h
    Air
    At 0h
    250ppm
    At 1h
    All for 18h of total exposure
    250ppm
    At 3h
  • 12. Analysis of Recovery
    Neurological Deficit Scores (NDS)
    Conducted at:
    Onset of reperfusion
    24hrs
    48hrs
    Scores range from 0 – 4
    Good
    Bad
  • 13. Results
  • 14. Also Analyzed
    Brain tissue
    Sliced into 2mm sections
    Stained to show metabolic activity
    Anterior
    Posterior
  • 15. Also Analyzed
    Brain Edema
    Ipsilateral and contralateral hemispheres separated
    % Brain Water = [(Wet – Dry)/Wet] x 100
  • 16. Not only in the Brain
    CO treatment in rat heart transplant model
    Akamatsu et al., 2004
    Comparison of CO therapy during reperfusion to:
    HO-1 activation
    Air inhalation
  • 17. Procedures
    Heart transplant
    Success/failure – % survival
    CO Exposure
    Varying exposure to donor, graft, and/or recipient
    400ppm
  • 18. Reagents and Results
  • 19. Results
    Highest survival rate
    Donor and graft exposure
    Donor, graft, and recipient exposure
    Interesting to note
    Donor and Recipient exposure only
  • 20. Other studies
    Similar results in liver and lung grafts
    Both in vivo and ex vivo
    (Amersi et al., 2002; Kohmoto et al., 2006)
    Upregulation of HO-1 system
    Increases CO endogenously
    (Amersi et al., 1999)
    Current goal
    Investigate mechanisms behind these results
  • 21. Limitations to current studies
    Small sample sizes
    Small animal models (rats and mice)
    Performed only on healthy specimens
    Although better, still low survival rate
    Need to improve before human trials
    Long term effects
    Dosage and duration of CO treatment
  • 22. Contradiction among studies
    Mechanisms of action
    Anti-inflammatory
    Anti-apoptotic
    Other HO-1 byproducts
  • 23. Conclusions & Implications
    Compared to no IRI treatment:
    CO therapy shows significantly improved tissue functioning
    Promising for future treatments of IRI
    Must further understand mechanism before clinical implementation
  • 24. References
    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.
    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.
    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.
    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.
    Zynalov E, Doré S. 2009. Low doses of carbon monoxide protect against experimental focal brain ischemia. Neurotoxicity Research. 15(2): 133-137.
  • 25. Acknowledgements
    Prof. Hancock
    Dr. Brown
    Capstone Classmates
    Teammates
  • 26. Questions?

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