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Inasmuch as long-chain polyunsaturated fatty acids (PUFA, metabolites of the essential n-3 and n-6 fatty acids) are known to modulate inflammation, we hypothesized that supplementation of formula with these compounds would prevent necrotizing enterocolitis (NEC) and intestinal inflammation in our neonatal rat model. Newborn rats were stressed with asphyxia and formula feeding, and randomly assigned to control formula, control with PUFA supplementation, and PUFA with nucleotides. Animals were followed for 72-96 h and assessed for death, gross and histologic NEC, intestinal apoptosis, endotoxemia, and intestinal mRNA synthesis of phospholipase A 2 -II (rate-limiting enzyme for platelet activating factor production), platelet activating factor receptor, and inducible nitric oxide synthase. We found that PUFA reduced the incidence of death and NEC compared with the other groups (NEC 8 of 24 versus 17 of 24 control and 13 of 23 PUFA ϩ nucleotides, p Ͻ 0.05). Furthermore, PUFA reduced plasma endotoxemia at 48 h (25 Ϯ 4 EU/mL versus 276 Ϯ 39 EU/mL in control and 170 Ϯ 28 EU/mL in PUFA ϩ nucleotide), intestinal phospholipase A 2 -II expression at 24 h, and platelet activating factor receptor expression at 48 h. Formula supplementation had no effect on apoptosis of intestinal epithelium or intestinal inducible nitric oxide synthase expression. Addition of nucleotides with PUFA abrogated the beneficial effects of PUFA on intestinal inflammation. We conclude that PUFA reduces the incidence of NEC and intestinal inflammation in a neonatal rat model. NEC is an overwhelming gastrointestinal emergency that primarily afflicts extremely low birth weight infants after the initiation of enteral feeding (1). The National Institute of Child Health and Human Development Network data show that despite improvements in many aspects of neonatal care, the incidence and severity of NEC has remained unchanged (2). Several clinical and basic science reports have identified that activation of the inflammatory cascade after the risk factors of ischemia-hypoxia, feeding, and bacterial colonization results in the final common pathway of intestinal necrosis that may occur in this high-risk population (3-5). Additional human and animal experimentation has defined an important association with the phospholipid inflammatory mediator PAF in the pathophysiology of NEC (6 -8). Studies in our laboratory using a well-described neonatal rat model have shown that PAF receptor blockade or enhanced intestinal PAF degradation via the enzyme PAF-acetylhydrolase reduces the incidence of NEC, thus emphasizing the importance of endogenous PAF in the cause (9, 10).Besides prematurity, the most consistent and important risk factor for NEC is enteral feeding. Although studies suggest that 90 to 95% of neonates in whom NEC develops have received

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