ALBERT

Description: Abstract 1538 Poster Board I-561 Circulating plasma hemoglobin contributes to major vasculopathies including pulmonary hypertension in patients who have sickle cell disease (SCD). There is an emerging concept that such vasculopathies are relatively mild because of activation of several cytoprotective pathways in SCD. The biochemical profile of plasma and the transcriptome of peripheral blood cells in patients who have SCD offer indirect support for this concept. Indeed, heme oxygenase-1 (HO-1), an acute phase enzyme that degrades heme into intermediates and byproducts with vasculoprotective properties is markedly elevated in mononuclear leukocytes of patients who have SCD. Nonetheless, the scope of the cytoprotective mechanisms of the lung and other organs impacted directly by sickle vasculopathies remain poorly appreciated. We previously identified an array of cytoprotective enzymes in lung endothelial cells chronically exposed to non-toxic concentrations of hemin in vitro. In this study, we examined the expression of NAD(P)H oxidase and candidate cytoprotective enzymes in two models of transgenic mice with SCD, and examined HO-1 expression in sickle chronic lung disease. Although NAD(P)H oxidase catalyzes reactive oxygen species generation by heme and is responsible for increased adhesion of leukocytes to the endothelium in SCD mice, there was no elevation of any of its subunits (gp91Phox and p22Phox, p47Phox, p67Phox and p40 Phox) in sickle mice lungs compared to hemizygote control mice lungs. Quantitative RT-PCR analysis revealed unexpectedly no difference in HO-1 mRNA level in sickle and non-sickle control lungs. On the contrary, analysis of the same tissues showed significantly higher NAD(P)H quinone oxidoreductase-1 (NQO1) mRNA level in both Berkeley and Townes knock-in sickle mice compared to controls (p