Nitric oxide (NO) levels plummet precipitously after lung transplantation (LTX), due to quenching by superoxide (O2-) in the reperfusion milieu. This can lead to graft thrombosis, leukostasis, and primary graft failure. In biological systems, however, alternative pathways are often activated when a primary homeostatic pathway fails, to contain the damage. Using a novel porphyrinic sensor capable of specifically detecting carbon monoxide (CO), we show that this diatomic gas which, like NO, binds to and activates heme-containing proteins, is produced at high levels in lungs subjected to ischemic stress at a time when NO levels plummet. CO given to rat LTX donors prior to lung harvest markedly improves posttransplant graft function and recipient survival. Heme oxygenase (HO) type 1, which catabolizes heme to liberate CO in vivo, is induced by ischemic stress. Mice null for the HO-1 gene exhibit exaggerated lung injury in response to ischemia but are rescued from ischemic lung injury by CO inhalation. Mechanistically, CO appears to restore vascular homeostasis by suppressing endothelial cell apoptosis in response to oxidant stress and by preventing ischemic induction of plasminogen activator inhibitor-1(PAI-1), thereby potentiating lysis of thrombus in postischemic microvessels. These data lead us to hypothesize that lung ischemia or preservation triggers expression of HO-1, which drives CO production to reestablish protective vascular homeostasis.
The aims of the current proposal are (1) to elucidate the functional role of endogenous HO-1 and CO in lung ischemia and transplantation; (2) to elucidate the mechanism(s) by which CO protects the ischemic lungs; and (3) to determine whether early HO-1/CO induction may limit the late development of obliterative after LTX. Studies will use orthotopic rat LTX and murine tracheal allograft models, HO-1 and PAI-1 gene-deleted mice (and endothelial cells derived therefrom) with or without reconstitution with CO, and unique CO/NO/O2- porphyrinic sensor technology to describe a novel HO- 1/CO mediated axis of ischemic pulmonary protection.
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