Molecular mechanisms contributing to necrotizing enterocolitis

Objective To examine the cellular mechanisms involved in the pathogenesis of necrotiz ing enterocolitis (NEC). Summary Background Data Necrotizing enterocolitis is a major cause of death and com plications in n eonates; the cellular mechanisms responsible for NEC are unknown. The induc ible form of cyclooxygenase (i.e., COX-2) is activated by the transcription factor nuclear factor (NF)-kappaB and is thought to play a role in inflamm ation. Methods Segments of perforated and adjacent uninvolved small intestine from neonate s with NEC were analyzed for COX-2 expression by immunohistochemistry. NEC was induced in weanling (18 days old) rats by occlusion of superior mesente ric vessels for 1 hour and intraluminal injection of platelet activating fa ctor (50 mug/kg). Small intestine was harvested for protein extraction. Wes tern immunoblot was performed to determine expression of COX-2. Gel shift a ssays were performed to assess NF-kappaB binding activity. Results Immunohistochemical analysis showed increased COX-2 protein expression in t he perforated intestinal sections of all 36 neonates but not in adjacent no rmal intestine. Increased expression of COX-2 protein and NF-kappaB binding activity was noted in the small intestine of weanling rats at 0 and 3 hour s after induction of NEC. Conclusions Increased COX-2 expression was identified in all neonatal intestinal segmen ts resected for perforated NEC. In addition, a coordinate induction of COX- 2 expression and NF-kappaB binding was noted in a rodent model of NEC. Thes e findings suggest that the COX-2/NF-kappaB pathway may play a role in the pathogenesis of NEC. Therapeutic agents that tar get this pathway may prove useful in the treatment or possible prevention of NEC.