Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice

Gastrointestinal (GI) tract damage by chemotherapy or radiation Limits their efficacy in cancer treatment. Radiation has been postulated to target epithelial stem cells within the crypts of Lieberkuhn to initiate the Lethal CII syndrome. Here, we show in mouse models that microvascular endothelial apoptosis is the primary Lesion Leading to stem cell dysfunction. Radiation-induced crypt damage, organ failure, and death from the CI syndrome were prevented when endothelial apoptosis was inhibited pharmacologically by intravenous basic fibroblast growth factor (bFGF) or genetically by deletion of the acid sphingomyelinase gene. Endothelial but not crypt, cells express FGF receptor transcripts, suggesting that the endothelial Lesion occurs before crypt stem cell damage in the evolution of the GI syndrome. This study provides a basis for new approaches to prevent radiation damage to the bowel.