Necrotizing enterocolitis (NEC) develops in up to 7600 U.S. infants annually, is leading cause of surgical emergency in neonates, and leads to death from peritonitis and overwhelming sepsis in 28-41% of cases. A specific etiology continues to elude investigators, although feeding, bacterial colonization, and hypoxia/ischemia predispose to NEC. Adult animal studies have noted an association of these factors with impairment of intestinal motor function. In the neonate, the effect of these factors on intestinal motor function as it relates to the pathogenesis of NEC is unknown. We propose to test the hypothesis that intestinal motor dysfunction is a key factor leading to the development of NEC in the neonate. Immature or impaired intestinal function could lead to disordered luminal transport, bacterial overgrowth, disrupted mucosal integrity, and the perforation and peritonitis characteristic of NEC. Specifically, we intend to examine small intestinal myoelectric activity (SIMEA) in the neonatal piglet and correlate it with GI hormone, catecholamine and beta-endorphin concentrations; bacterial colonization patterns; and intestinal histology under the following conditions: 1) during maturation from birth through weaning; 2) in response to various feeding volumes/schedules during normoxemia, 3) in response to various feeding volumes/ schedules during asphyxia, 4) following pharmacologic blockade of asphyxia-induced catecholamine and/or B- endorphin effects of SIMEA using a) phentolamine and propranolol to block alpha- and beta-adrenergic activities, b) using naloxone to block beta-endorphin effects, and c) using a combination of all three drugs to block catecholamine and beta-endorphin effects. The proposed studies will provide a scientific basis upon which to compare the effects of feeding and/or asphyxia on SIMEA in neonates, and will thus-contribute to insight regarding the pathophysiology of NEC. They will allow us to more effectively predict high-risk infants and potentially intervene to prevent or treat this condition which contributes to significant morbidity and mortality.
