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Necrotizing enterocolitis (NEC) is a devastating gastrointestinal disease of prematurity that typically develops after the administration of infant formula, suggesting a link between nutritional components and disease development. One of the most significant complications that develops in patients with NEC is severe lung injury. We have previously shown that the administration of a nutritional formula that is enriched in pre-digested triglycrides that do not require lipase action can significantly reduce the severity of NEC in a mouse model. We now hypothesize that this ‘pre-digested fat system (PDF)’ may reduce NEC-associated lung injury. In support of this hypothesis, we now show that rearing newborn mice on a nutritional formula based on the ‘pre-digested fat (PDF) system’ promotes lung development, as evidenced by increased tight junctions and surfactant protein expression. Mice who were administered this ‘PDF fat system’ were significantly less vulnerable to the development of NEC-induced lung inflammation, and the administration of the ‘PDF fat system’ conferred lung protection. In seeking to define the mechanisms involved, the administration of the PDF system’ significantly enhanced lung maturation and reduced the production of reactive oxygen species (ROS). These findings suggest that the PDF system protects the development of NEC-induced lung injury through effects on lung maturation and reduced reactive oxygen species in the lung, and also increase lung maturation in non-NEC mice.

Sepsis is a major cause of mortality, and dysregulation of the immune response plays a central role in this syndrome. H2S, a recently discovered gaso-transmitter, is endogenously generated by many cell types, regulating a number of physiologic processes and pathophysiologic conditions. We report that H2S increased survival after experimental sepsis induced by cecal ligation and puncture (CLP) in mice. Exogenous H2S decreased the systemic inflammatory response, reduced apoptosis in the spleen, and accelerated bacterial eradication. We found that C/EBP homologous protein 10 (CHOP), a mediator of the endoplasmic reticulum stress response, was elevated in several organs after CLP, and its expression was inhibited by H2S treatment. Using CHOP-knockout (KO) mice, we demonstrated for the first time, to our knowledge, that genetic deletion of Chop increased survival after LPS injection or CLP. CHOP-KO mice displayed diminished splenic caspase-3 activation and apoptosis, decreased cytokine production, and augmented bacterial clearance. Furthermore, septic CHOP-KO mice treated with H2S showed no additive survival benefit compared with septic CHOP-KO mice. Finally, we showed that H2S inhibited CHOP expression in macrophages by a mechanism involving Nrf2 activation. In conclusion, our findings show a protective effect of H2S treatment afforded, at least partially, by inhibition of CHOP expression. The data reveal a major negative role for the transcription factor CHOP in overall survival during sepsis and suggest a new target for clinical intervention, as well potential strategies for treatment.