PULMONARYHYPERTENSIONIN SICKLE CELL DISEASE

University Of Southern California, Los Angeles CA

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Abstract

Chronic lung disease and pulmonary hypertension are complications of the sickle diseases that are increasingly recognized and are associated with considerable morbidity and mortality. Standard therapy with oxygen and a hypertransfusion regimen have not demonstrated efficacy in prolonging survival in such patients, indicating a need for new approaches to management. Both hydroxyurea and I-arginine have the potential for increasing endogenous production of NO within the pulmonary vasculature and may have beneficial effects on oxygenation and pulmonary vascular resistance in patients with chronic lung disease and pulmonary hypertension. In addition, hydroxyurea improves red blood cell hemorheological properties and microvascular blood flow and thus combined therapy may impact smooth muscle hyperplasia in damaged pulmonary microvasculature. We hypothesize that beneficial clinical responses may accrue to patients with sickle chronic lung disease and pulmonary hypertension as a result of increases in NO generated by oral administration of hydroxyurea and/or I-arginine. We further hypothesize that these beneficial effects are consequent to modulation of vasoactive peptides (ET-1) and adhesion molecules (I-CAM-I, V-CAM-I). The proposed research project is a phase II, randomized clinical trial designed to determine the effect of the NO donor I-arginine and hydroxyurea, either singly or in combination, on the biologic and clinical features of sickle cell disease patients with chronic lung disease and pulmonary hypertension. We further propose to characterize the effects of this treatment strategy on a broad range of RBC and hemorheologic properties in SCD,and to determine its efficacy in ameliorating chronic lung disease and pulmonary hypertension in these patients.