? The lungs are extremely vulnerable to ischemia/reperfusion injury, with up to 20% incidence of primary graft failure and 50% incidence of obliterative bronchiolitis (OB). Poor preservation leads to decline in nitric oxide (NO) and second messenger signals leading to early graft vascular failure. Heme oxygenase-1 (HO-1), which cleaves heme to generate carbon monoxide (CO), is induced by lung ischemia and exerts a protective counterbalance to NO dissipation. Inhalation of small amounts of a respiratory poison (CO) improves outcomes following experimental lung ischemia and reduces OB. CO appears to suppress ischemic induction a """"""""master switch"""""""" transcription factor, early growth factor-1 (Egr-1) which otherwise triggers expression of divergent families of genes driving inflammation and thrombosis. Studies will focus on the role of biological gases, NO and CO, in lung preservation and OB, using lung transplant in rats and a novel airflow-permissive airway transplant model in mice. Signaling mechanisms by which CO suppresses expression of Egr-1 and its inflammatory/thrombotic gene targets will also be examined using innovative nanosensors (to measure CO, NO, 02"""""""", and ONOO""""""""), gene knockout mice (HO-1, Egr-1, iNOS, and PAI-1), and exposure of cells and animals to CO and NO under simulated ischemic (hypoxic) conditions.
The Aims are to (1) determine how biological gases modulate vascular mechanisms of primary lung graft failure; (2) establish the signaling mechanism(s) by which endogenous CO limits development of a procoagulant and proinflammatory vascular phenotype, focusing on guanylate cyclase activation and Egr-1 suppression; (3) determine how NO and CO modulate pathological development of lymphocytic bronchitis leading to OB, and the contribution of ischemic injury; and (4) determine whether inhaled CO passivizes immune or thrombotic effector cells during pulmonary transit or whether topical gas exposure is required for preservation enhancement and protection from OB. Experiments will shed new light on the role of biological gases and secondary signaling cascades as endogenous mechanisms of pulmonary vascular and airway cytoprotection following lung preservation. These studies may lead to harnessing inspired """"""""toxic"""""""" gases to improve outcomes after lung transplantation. ? ?
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