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 Lieberkühn to initiate the lethal GI 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 GI 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.
Paris
F
F
Laboratory of Signal Transduction and, Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
Fuks
Z
Z
Kang
A
A
Capodieci
P
P
Juan
G
G
Ehleiter
D
D
Haimovitz-Friedman
A
A
Cordon-Cardo
C
C
Kolesnick
R
R
D000818:Animals; D017304:Annexin A5 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D001853:Bone Marrow / Q000528:radiation effects; D016026:Bone Marrow Transplantation; D002196:Capillaries; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000528:radiation effects*; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D006801:Humans; D020287:In Situ Nick-End Labeling; D007413:Intestinal Mucosa / Q000098:blood supply / Q000166:cytology / Q000473:pathology / Q000528:radiation effects*; D007422:Intestines / Q000098:blood supply / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009369:Neoplasms / Q000473:pathology / Q000532:radiotherapy; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D013108:Sphingomyelin Phosphodiesterase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000528:radiation effects; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism; D014916:Whole-Body Irradiation
D017304:Annexin A5; D017468:Receptors, Fibroblast Growth Factor; D016159:Tumor Suppressor Protein p53; D005346:Fibroblast Growth Factors; D013108:Sphingomyelin Phosphodiesterase