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Biomedical subjects

C W Houchen

Publications and source records attributed to C W Houchen.

4 recordsLinked to original sources

Clinical implications of prostaglandin inhibition in the small bowel.

NSAID-induced intestinal toxicity is more common than previously recognized and may have clinically significant sequelae, especially in elderly arthritic patients. Increased awareness of the potential intestinal complications associated with prostaglandin inhibition is required for early recognition and appropriate management. An increase in the level of suspicion by physicians may lead to earlier diagnosis and subsequent discontinuation of the offending NSAID; this is important in that discontinuation of the offending agent may be preferable to multiple endoscopic radiologic and surgical procedures in the patient with obscure blood loss and anemia. Appropriate diagnosis in selected patients may prevent the increased morbidity and mortality associated with small intestinal surgery. The emergence of selective COX-2 inhibitors likely will bring this issue to the forefront because it will become increasingly important to determine the effects of these agents on the small intestine and colon, in addition to their effects on the gastroduodenal mucosa. The new generation of selective COX-2 inhibitors may offer a potential therapeutic advantage over the nonselective NSAIDs with respect to their intestinal toxicity. Well-designed safety trials that have intestinal injury as a predefined end point will provide important information as to the overall gastrointestinal safety of these compounds. These agents must be evaluated with respect to their overall safety profile and not just by their gastrointestinal safety. Nevertheless, these agents are continuing to provide new directions for exciting basic and clinical scientific investigation.

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Disruption of cyclooxygenase-1 gene results in an impaired response to radiation injury.

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 gamma-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. PGE(2) 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 PGE(2) 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 PGE(2), 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.

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FGF-2 enhances intestinal stem cell survival and its expression is induced after radiation injury.

Fibroblast growth factors (FGFs) have mitogenic activity toward a wide variety of cells of mesenchymal, neuronal, and epithelial origin and regulate events in normal embryonic development, angiogenesis, wound repair, and neoplasia. FGF-2 is expressed in many normal adult tissues and can regulate migration and replication of intestinal epithelial cells in culture. However, little is known about the effects of FGF-2 on intestinal epithelial stem cells during either normal epithelial renewal or regeneration of a functional epithelium after injury. In this study, we investigated the expression of FGF-2 in the mouse small intestine after irradiation and determined the effect of exogenous FGF-2 on crypt stem cell survival after radiation injury. Expression of FGF-2 mRNA and protein began to increase at 12 h after gamma-irradiation, and peak levels were observed from 48 to 120 h after irradiation. At all times after irradiation, the higher molecular mass isoform ( approximately 24 kDa) of FGF-2 was the predominant form expressed in the small intestine. Immunohistochemical analysis of FGF-2 expression after radiation injury demonstrated that FGF-2 was predominantly found in the mesenchyme surrounding regenerating crypts. Exogenous recombinant human FGF-2 (rhFGF-2) markedly enhanced crypt stem cell survival when given before irradiation. We conclude that expression of FGF-2 is induced by radiation injury and that rhFGF-2 can enhance crypt stem cell survival after subsequent injury.

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