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1 Division of Gastroenterology, Washington University, Saint Louis, Missouri; and 2 Division of Gastroenterology and Hepatology, University of Virginia, Charlottesville, Virginia
Prostaglandins may play an important role in
regulating normal renewal of gastrointestinal epithelium, epithelial
injury repair, and initiation or progression of intestinal neoplasia. Synthesis of prostaglandins is catalyzed by either of two
cyclooxygenase isoforms, Cox-1 and Cox-2. Cox-1 is the predominant
cyclooxygenase isoform found in the normal intestine. In contrast,
Cox-2 is present at low levels in normal intestine but is elevated at
sites of inflammation and in adenomas and carcinomas. To determine
directly whether prostaglandins synthesized by Cox-1 or Cox-2 regulate crypt epithelial cell fate after genotoxic or cytotoxic injury, we
examined apoptosis, prostaglandin synthesis, and crypt stem cell
survival after 
-irradiation in Cox-1
/ and
Cox-2/ mice. Cox-1/ mice had increased
crypt epithelial cell apoptosis and decreased clonogenic stem cell
survival compared with wild-type littermates. PGE2
synthesis was also diminished in Cox-1/ mice compared
with wild-type controls in unstressed intestine and after radiation
injury. In contrast, apoptosis, stem cell survival, and intestinal
PGE2 synthesis in Cox-2/ mice after
irradiation were the same as in wild-type littermates. Crypt stem cell
survival after irradiation was inhibited by a highly specific
neutralizing antibody to PGE2, suggesting that this
prostaglandin mediates stem cell fate in vivo. These data suggest that
prostaglandins synthesized by Cox-1 regulate multiple steps that
determine the fate of crypt epithelial cell after genotoxic or
cytotoxic injury.
cyclooxygenase; ionizing radiation; prostaglandin E2; intestinal epithelium; gastrointestinal malignancy
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