Early postnatal dexamethasone diminishes transforming growth factor alpha localization within the ileal muscularis propria of newborn mice and extremely low-birth-weight infants

Focal small bowel perforation (FSBP) occurs most commonly in the ileum of e xtremely low-birth-weight (ELBW) infants. Early postnatal dexamethasone (EP D) administration results in an increased risk for FSBP in this patient pop ulation, but the mechanism by which this occurs is unknown. Infants with FS BP have healthy mucosa but thinned smooth muscle, suggesting a mechanism in volving the muscularis propria for these perforations. One explanation for these findings would be that dexamethasone alters the tissue availability o f pertinent growth factors to the smooth muscle. To explore this possibilit y, we administered dexamethasone or saline by intraperitoneal injection to newborn mice for 3 days (dosed at 1 mug/g of body weight/day) to simulate E PD protocols. The animals were sacrificed after 72 h of treatment and their ileums harvested and prepared for microscopy. Immunolocalization was perfo rmed for three related growth factors (epidermal growth factor [EGF], hepar in-binding EGF [h-EGF], and transforming growth factor a [TGF-alpha]) and t heir common receptor. We found TGF-alpha to be abundant and discretely loca lized in the muscularis propria in control animals but to be diminished in dexamethasone-treated animals. EGF-receptor immunostaining was also decreas ed with dexamethasone but there was minimal to no detection of EGF or h-EGF in either treatment condition. Surgical and autopsy specimens of the ileum were obtained from seven ELBW infants who either received EPD or not. Thes e tissues were used for immunolocalization of the same growth factors and s imilar distributions for TGF-alpha were observed in several of these cases. These findings are consistent with an autocrine role for TGF-alpha in ilea l smooth muscle proliferation and suggest a mechanism by which EPD might me diate smooth muscle thinning.