ENDOTHELIN-1 PRODUCTION DURING THE ACUTE CHEST SYNDROME IN SICKLE-CELL DISEASE

To investigate the role of the endothelial-derived vasoactive mediator endothelin (ET-1) in the acute chest syndrome (ACS), we incubated bov ine pulmonary artery endothelial cells (BPAEC) with red blood cells (e quivalent to a hematocrit of 20%) and/or autologous plasma (1:10 dilut ion) from two patients during ACS and during routine clinic visits. Ce llular RNA was analyzed for ET-1 transcripts by Northern analysis and ET-1 protein levels in BPAEC supernatants and in plasma measured by ra dioimmunoassay, ET-1 mRNA expression and protein levels increased in B PAEC exposed to plasma obtained during ACS; in contrast, exposure to p lasma obtained during routine clinic visits did not alter BPAEC ET-1 m RNA expression or protein levels. Plasma ET-1 level was elevated durin g ACS, decreased during resolution, and remained slightly elevated dur ing routine clinic visits. Plasma obtained from one patient 4 d prior to hospitalization for vasoocclusive crisis contained the highest ET-1 level and markedly increased BPAEC ET-1 mRNA expression and protein l evels. In both patients, BPAEC ET-1 mRNA and protein expression in vit ro and plasma ET-1 levels in vivo correlated with stage of disease and occurred in the absence of direct erythrocyte contact in vitro. These observations suggest that ET-1 production contributes to development of ACS.