| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2009: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Research Abstract |
Carbon monoxide (CO) is produced endogenously as a byproduct of heme catalysis, and has been shown to provide protection against ischemia-reperfusion injury (IRI) in a variety of organs in murine models. Since CO is also known to be a toxic gas, translational research using large animals is essential prior to its use in the clinic. To attempt CO to apply for the clinical setting, we examined whether (1) perioperative CO inhalation to both donor and recipient prolongs lung graft survival (2) donor treatment alone is sufficient to prolong graft survival and (2) postoperative CO therapy has additional survival benefits in MHC-inbred CLAWN miniature swine.
Eighteen CLAWN swine received fully MHC mismatched lungs with 12 days of tacrolimus (days 0-11 ; 35-45 ng/ml). In Group 1 (n=6), recipients received tacrolimus alone. In Group 2 (n=5), both donors and recipients inhaled 200-250 ppm CO (180 min for donors ; 390 min for recipients until 2-hr reperfusion). In Group 3 (n=4), only donors were
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treated with CO for 180 min. In Group 4 (n=3), recipients were additionally given daily 1-hour 250 ppm CO for 14 postoperative days.
All recipients in Group 1 uniformly rejected their grafts by postoperative day 63 with development of cytotoxic antidonor antibodies. In contrast, 4 out of 5 recipients in Group 2 accepted their grafts beyond 63 days. Short-term CO treatment only with donor (Group 3) was effective in prolonging allograft survival. Three out of 4 recipients accepted their grafts beyond 63 days with the longest survivor lasting 150 days. In Group 4, two out of 3 recipients maintained their grafts for 91 days ; however, postoperative CO did not prolong graft survival compared to Group 2. Development of antidonor-antibodies and donor-specific responsiveness by MLR and CML assays was delayed in animals that received CO therapy. Furthermore, fewer inflammatory cell infiltrates and injuries of endothelial cells were seen on POD2 biopsies, and serum concentrations of the pro-inflammatory cytokines (IL-1β, IL-6) also decreased in Group 2-4.
These data suggest that donor CO treatment alone is sufficient to improve lung allograft survival in a clinically relevant large animal model. Donor cytoprotective preconditioning with CO during organ harvest or preservation could be accomplished in a clinical setting, potentially improving graft survival with little risk of adverse effects on the recipient. Less
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