Timing of Lethality From Gastrointestinal Syndrome in Mice Revisited

Anti-ceramide antibody prevents the radiation gastrointestinal syndrome in mice

“…While conventional radiobiology considers unrepaired or misrepaired DNA doublestrand breaks in stem cell clonogens (SCCs) as autonomous lesions leading to irreversible tissue injury, our recent studies have challenged this paradigm, presenting genetic evidence that acute endothelial damage also plays a major role in GI tract injury (4)(5)(6). Within minutes of radiation exposure, endothelial acid sphingomyelinase (ASMase) is activated, catalyzing ceramide generation on the external plasma membrane of mouse and human endothelium to initiate apoptotic signaling (7,8).…”

“…Early evidence indicates that vascular compromise, consequent to endothelial cell apoptosis, impairs radiation-injured SCC DNA damage repair, resulting in SCC demise. In several mouse strains, endothelial apoptosis occurs between 8 and 15 Gy (4, 6), which encompasses doses that cause both sublethal (≤14 Gy) and lethal (≥15 Gy) GI tract injury (5), beginning at 1 hour and peaking at 4 to 6 hours after irradiation (4,6,11). Attenuation of intestinal endothelial apoptosis by genetic inactivation of ASMase-mediated ceramide generation enhances SCC survival, facilitating repair of crypt damage and rescue of animals from GI lethality (4,6).…”

Accelerated hematopoietic syndrome after radiation doses bridging hematopoietic (H-ARS) and gastrointestinal (GI-ARS) acute radiation syndrome: Early hematological changes and systemic inflammatory response syndrome in minipig

“…A continuum in the development of symptoms and pathologies has been proposed over the years, and covers hematopoietic (H-ARS), gastrointestinal (GI-ARS), cutaneous and central nervous system (CNS) syndromes. Nevertheless, experimental evidence from several mouse models (Mason et al 1989, Terry and Travis 1989, Rotolo et al 2009) has revealed an intermediate syndrome between H-ARS and GI-ARS, the socalled accelerated bone marrow syndrome (AH-ARS), where lethality manifested in less than 10 -12 days at doses between 14.7 Gy and 17.95 Gy (doses suffi cient to cause 10% and 90% death, respectively). In these mice, bone marrow damage contributed to death, as supported by the fact that in bone marrow-protected mice, pure gastrointestinal lethality was observed only at much higher doses ( Ն 19 Gy).…”

Radiation decreases murine small intestinal HCO3−secretion

“…The pH-stat on irradiated mice showed reduced HCO 3 7 secretion compared to non-irra-diated mice and was mostly lumen Cl 7 -independent. Death within two weeks following irradiation is due to acute gastrointestinal syndrome (AGS), a component of acute radiation syndrome (Dubois and Walker 1988, Mason et al 1989, Terry and Travis 1989, Potten 1990, Roberts et al 2003, Brown 2008, Rotolo et al 2009). Intestinal epithelial cells are replaced at a rate to match their loss resulting from normal maturation and differentiation, which allows for efficient fluid and electrolyte homeostasis by progenitor cells located in the crypts of Lieberkuhn (Cheng andLeblond 1974, Potten et al 1997).…”