Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Animals
-
Annexin A5 / metabolism
-
Apoptosis* / drug effects
-
Apoptosis* / radiation effects
-
Bone Marrow / radiation effects
-
Bone Marrow Transplantation
-
Capillaries
-
Endothelium, Vascular / drug effects
-
Endothelium, Vascular / pathology
-
Endothelium, Vascular / radiation effects*
-
Fibroblast Growth Factors / pharmacology
-
Humans
-
In Situ Nick-End Labeling
-
Intestinal Mucosa / blood supply
-
Intestinal Mucosa / cytology
-
Intestinal Mucosa / pathology
-
Intestinal Mucosa / radiation effects*
-
Intestines / blood supply
-
Intestines / pathology
-
Intestines / radiation effects*
-
Mice
-
Mice, Inbred C57BL
-
Neoplasms / pathology
-
Neoplasms / radiotherapy
-
Receptors, Fibroblast Growth Factor / metabolism
-
Sphingomyelin Phosphodiesterase / deficiency
-
Sphingomyelin Phosphodiesterase / genetics
-
Sphingomyelin Phosphodiesterase / metabolism
-
Stem Cells / radiation effects
-
Tumor Suppressor Protein p53 / deficiency
-
Tumor Suppressor Protein p53 / metabolism
-
Whole-Body Irradiation
Substances
-
Annexin A5
-
Receptors, Fibroblast Growth Factor
-
Tumor Suppressor Protein p53
-
Fibroblast Growth Factors
-
Sphingomyelin Phosphodiesterase