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Departments of 1 Molecular Biology and Pharmacology and 2 Surgery, Washington University School of Medicine, St. Louis, Missouri 63110
Little is known
about the effects of ischemia-reperfusion on the inductive,
commitment, or execution phases of apoptosis. We have created a
genetically defined model to study the response of small intestinal
epithelial cells to ischemia-reperfusion injury as a function
of their proliferative status and differentiation. Occlusion of the
superior mesenteric artery for 20 min in adult FVB/N or C57BL/6 mice
results in the appearance of TUNEL-positive apoptotic cells in the
jejunal epithelium within 4 h, with a maximum response occurring at 24 h. Stimulation of apoptosis is greater in postmitotic, differentiated
epithelial cells located in the upper portions of villi compared with
undifferentiated, proliferating cells in the crypts of Lieberkühn
(7-fold vs. 2-fold relative to sham-operated controls). Comparisons of
p53+/+ and
p53
/ mice
established that the apoptosis is p53 independent. To further characterize this response, we generated FVB/N transgenic mice that
express human Bcl-2 in epithelial cells distributed from the base of
crypts to the tips of their associated villi. The fivefold elevation in
steady-state Bcl-2 concentration is not accompanied by detectable
changes in the levels or cellular distributions of the related
anti-apoptotic regulator Bcl-xL or
of the proapoptotic regulators Bax and Bak and does not produce
detectable effects on basal proliferation, differentiation, or death
programs. The apoptotic response to ischemia-reperfusion is
reduced twofold in the crypts and villi of transgenic mice compared
with their normal littermates. These results suggest that both
undifferentiated and differentiated cells undergo a commitment phase
that is sensitive to Bcl-2. Forced expression of Bcl-2 also suppressed
the p53-dependent death that occurs in proliferating crypt epithelial
cells following 
-irradiation. Thus suppressibility by Bcl-2
operationally defines a common feature of the apoptosis induced in the
crypt epithelium by these two stimuli.
programmed cell death; intestinal epithelial differentiation; -irradiation
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