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289 TUMOR NECROSIS FACTOR ALPHA LEVELS IN RESPONSE TO PATHOGENIC STIMULI IN THE DEVELOPING GUT OF EMBRYONIC AND NEWBORN MICE.

Background Prematurity is the most important risk factor for necrotizing enterocolitis (NEC), a significant cause of neonatal morbidity and mortality. Premature infants may exhibit a high risk of NEC due to developmental immaturity of the gastrointestinal tract and inability to respond appropriately to pathogenic stimuli, as compared to a more mature intestine. Purpose We used TNF-alpha as a proinflammatory marker to assess the inflammatory response to pathogenic bacteria and their products, during late embryonic and early postnatal gut development. Methods Timed pregnancies in C57BL/6J mice allowed accurate dating of neonatal mice. These mice were sacrificed at embryonic day 18 (sterile gut) and at postnatal days +16 and +21 for development of an ex vivo system of mouse intestinal infection. Intestines were isolated in 2 cm sections and surgically opened lengthwise to expose epithelia. Intestinal sections were washed in warm HBSS+ and then treated with or without wild-type Salmonella typhimurium or LPS in RPMI media at 37C, 5% CO2 for 30, 60, 120, and 180 minutes. Media was collected for further analysis. Proinflammatory response was measured by ELISA for TNF-alpha. Summary of Results Older mice demonstrated a larger proinflammatory response, as measured by increased TNF-alpha secretion, as compared to the embryonic day 18 mice. Peak response occurred 2-3 hours after being stimulated by the bacteria or LPS. Conclusions Our preliminary data indicate that the immature intestine is not appropriately responding to pathogenic stimuli. We further speculate that initial colonization of the neonatal intestine with normal flora may play a key role in regulating this response. Further experiments with gnotobiotic mice will help delineate the exchange of prokaryotic and eukaryotic signals involved.