Backgroud: Necrotizing enterocolitis (NEC), a disease of premature infants, is a leading cause of morbidity and mortality in neonatal intensive care units. Its known predisposing factors include prematurity, enteral feeding, and infection, but the pathogenesis is still obscure.

Data sources and Results: Several animal models of NEC have been established in adult and neonatal rats and mice. Endogenous mediators, especially platelet-activating factor (PAF), play a pivotal role in NEC. Injection of PAF results in intestinal necrosis, and PAF antagonists prevent the bowel injury induced by endotoxin, hypoxia, or tumor necrosis factor-α (TNF) in adult rats. PAF antagonists or PAF-acetylhydrolase, the enzyme degrading PAF, also ameliorate the pathology of the neonatal model induced by hypoxia and enteral feeding. Human patients with NEC have elevated levels of plasma PAF and decreased PAF-acetylhydrolase. However, to exert its injurious action, PAF requires the presence of commensal bacteria in the intestine. The initial event in our models of NEC is probably polymorphonuclear leukocytes (PMN) activation and adhesion to venules in the intestine, probably in response to local PAF release. Other molecules and mediators taking part in the process include NF-κB, TNF, chemokines (especially MIP-2/CXCL2), and the complement system, leading to a local inflammatory reaction. Subsequent release of vasoconstrictors and the consequent mesenteric vasoconstriction result in splanchnic ischemia and reperfusion. Toxins from commensal bacteria (e.g., endotoxin) enter the intestinal tissue during local mucosal barrier breakdown, and synergize with PAF and TNF to amplify the inflammation. Reactive oxygen species produced by the activated leukocytes and by intestinal epithelial xanthine oxidase may be the final effector for tissue injury. Protective mechanisms include nitric oxide produced by the constitutive (mainly neuronal) nitric oxide synthase (which maintains intestinal perfusion and the integrity of the mucosal barrier), and the innate immune response, enhanced by indigenous probiotics such as Bifidobacteria and Lactobacilli.

Conclusions: The eventual development of severe bowel necrosis depends on the balance between the injurious and the protective mechanisms. The injurious includes various pro-inflammatory molecules such as PAF, leukotrienes, TNF, chemokines, the complement system, vasoconstrictors, adhesion molecules, xanthine oxidase, reactive oxygen species, NF-κB and products of commensal bacteria such as lipopolysaccharide. The protective mechanisms include neuronal nitric oxide synthase, PAF acetylhydrolase, and probiotics.

Key words: necrotizing enterocolitis; platelet-activating factor; tumor necrosis factor; nuclear factor kappa B; chemokines; reactive oxygen species; nitric oxide synthesis; probiotics; intestines