The goal of the proposed research is to study the role of hypoxia, toxic oxygen species and pneumonia in the acute lung injury seen in sickle cell disease (SCD) . Previous studies done using sickle red blood cells (SRBCS) compared to normal human RBCs have demonstrated that auto-oxidation of hemoglobin in SRBCs result in twice the amount of toxic oxygen species produced and that SRBCs have an overall reduced antioxidant activity. In addition, the process of sickle-unsickle cycling lends to the probability that ischemia-reperfusion tissue injury is a second source of oxidant-production which possibly contributes to acute lung injury in sickle cell disease. The initial studies will characterize the ability of the SRBC to protect the lung from oxidant lung- injury mediated via ischemia-reperfusion and hyperoxia. Preliminary studies suggest that local ischemia-reperfusion can result in lung injury remote to initial insult and this injury will be further characterized. Subsequent studies will assess the role of pneumococcal pneumonia in triggering acute lung injury in sickle cell disease. In this proposal, the isolated rat lung perfusion model will be employed in which pulmonary hemodynamics and vascular permeability can be assessed. (See Preliminary Data). The results of these studies should better define the mechanisms of acute lung injury in SCD and hopefully improve our understanding of its pathogenesis. The environment for the proposed work is the University of South Alabama Medical Center which was recently awarded a Sickle Cell Center grant. Thus, the population base and environment are optimal for this work and my career development as a clinical investigator.
