Development of Glucocorticoid-Responsiveness in Mouse Intestine

Abstract

There are conflicting data from human studies regarding the ability of exogenous glucocorticoids to stimulate maturation of the small intestine. The discrepancies may relate to differences in hormone doses and age administered. To explore this general concept, we have used a mouse model to determine intestinal responsiveness to dexamethasone (DEX) at various times during development. We first showed that trehalase mRNA is a sensitive marker of intestinal maturation in the mouse; being undetectable (by Northern blotting) in the prenatal period, expressed at low levels during the first 2 postnatal weeks and then displaying a marked increase in the 3rd postnatal week. DEX was unable to elicit detectable trehalase mRNA in fetal mice, but caused significant increases in the postnatal period. The use of a range of DEX doses (0.0125-2.5 nmol/g BW per day) established that there is no change in sensitivity between the 1st and 2nd postnatal weeks, but there is a significant increase in maximal responsiveness of trehalase mRNA to the hormone. Similar results were obtained when sucrase-isomaltase mRNA was assayed in the same animals. Thus, in this rodent model, there appears to be at least three phases in the DEX responsiveness of the developing intestine: an early phase (prenatal) when DEX is unable to elicit intestinal maturation; then a phase (first postnatal week) of modest responsiveness; then a transition to increased responsiveness. These findings point to the need for careful attention to dose and age in analyses of glucocorticoid effects in human infants. Glucocorticoids have become an important component in the pharmacologic treatment of prematurity because of their maturational effects on certain tissues. In the lung, for example, corticosteroid therapy is central to the prevention of respiratory distress syndrome. Interestingly, several clinical trials using exogenous glucocorticoids in the treatment of prematurity also demonstrated a decreased incidence of necrotizing enterocolitis (NEC) in steroid-treated infants (1-3). In addition, Halac and coworkers conducted a prospective human study of the effect of DEX on the incidence of NEC and found a significant reduction in NEC among neonates receiving either prenatal or postnatal steroid (4). As NEC is typically associated with immaturity (5-7), these findings suggest that exogenous glucocorticoid may exert a maturational effect on the intestine. However, not all trials observed decreased NEC (2). Likewise, although investigators have found significant maturation of intestinal motility (8) and permeability (9) in premature infants whose mothers received prenatal glucocorticoid, another study reported no effect on lactase maturation (10). The latter in vivo observation is in contrast to several studies that have shown elevation of lactase activity in response to glucocorticoid treatment in explant cultures of human fetal intestine (11-13). We hypothesize that such seemingly disparate results may be explained by differences in dosages and timing of corticosteroid tr...

Hydrocortisone induces changes in gene expression and differentiation in immature human enterocytes

“…11). In fact, in rodents, adrenalectomy during the suckling period retards enterocyte development in the small intestine, whereas the early administration of exogenous HC may cause a precocious maturation of the gut (14,23,31). The molecular mechanisms of HC action(s) in these systems are not well understood.…”

The cellular repressor of E1A-stimulated genes mediates glucocorticoid-induced loss of the type-2 IGF receptor in ileal epithelial cells

“…However, there is a limited temporal window in which this endocrine stimulus is optimal (Solomon et al 2001). In contrast, we have previously reported a significant increase in ileal epithelial and goblet cell numbers when newborn mice are treated with early postnatal dexamethasone (DEX) (Gordon et al 2001a), suggesting a proliferative mechanism of hypertrophy that is potentially ever present in the neonate.…”

“…Glucocorticoids trigger mucosal maturation during weaning and can accelerate the process if given exogenously in the week immediately prior to weaning (Henning & Sims 1979, Oesterreicher et al 1998, Solomon et al 2001. However, there is a limited temporal window in which this endocrine stimulus is optimal (Solomon et al 2001).…”

IGF-I Accelerates Ileal Epithelial Cell Migration in Culture and Newborn Mice and May Be a Mediator of Steroid-Induced Maturation

“…However, administration of glucocorticoid in the first days of life results in a precocious maturation (characterized in the newborn mouse by mucosal growth concomitant with bowel wall thinning) (3). Further comparison between the precocious and the accelerated models of maturation in mouse pups reveals attenuated expression of maturation-related digestive enzymes in the younger animals (4). In addition to these developmental aberrancies, precocious maturation has also been linked to a neonatal disease state.…”

“…To test the hypothesis that IGF-I is a mediator of DEX effect upon ileal epithelial cells, we sought an easily quantifiable and robust experimental outcome associated with precocious mat-uration [as opposed to the digestive enzymatic markers that show attenuated up-regulation in vivo and dependency upon soluble fibroblast-derived factors in culture (4,9,10)]. Acceleration of intestinal epithelial cell migration up the villus is an early and transient maturational phenomenon that occurs even when the near-term fetus is exposed to glucocorticoids through maternal administration (11).…”