These studies focus on the role of the microvasculature in tissue damage. We have shown that endothelium in the lung, gut, and brain are markedly resistant to radiation-induced apoptotic death in the absence of acid sphingomyelinase. Acid sphingomyelinase catalyzes the hydrolysis of sphingomyelin to the pro-apoptotic second messenger ceramide. In the gastrointestinal (GI) tract, ionizing radiation induces rapid micorvascular endothelial apoptosis. Inhibition of this event, by intravenous injection of the endothelial survival factor bFGF or by genetic deletion of acid sphingomyelinase, prevented crypt dysfunction and death from the GI syndrome. This syndrome is a major chemotoxicity and radiotoxicity limiting the effective use of these therapies for the treatment of cancer. Recent investigations have focused on the potential role of acid sphingomyelinase in angiogenic endothelial responses to ionizing radiation.
