Presented at the Neonatal Society 2002 Autumn Meeting.

Fagbemi AO, Ashwood P, Torrente F, Lakhoo K*, Murch S

Centre for Paediatrics Gastroenterology, Royal Free Hospital, London and John Radcliffe Hospital, Oxford*, UK

The purpose of study: The aetiology of neonatal necrotising enterocolitis (NEC) is unknown. However animal models suggest that both luminal contents and gut dysmotility are critical triggers of an inflammatory cascade. Importantly, targeted disruption of enteric neural microglial cells in transgenic animals induces spontaneous NEC-like lesion in response to the luminal flora, with ileal perforation and death. We thus aimed to study potential immune-neural interactions in vascular and neural structures, particularly glial cells, in cases of human NEC.

Methods and Subject: We studied full thickness resected specimens from 18 preterm infants with acute NEC (median age 17 days, range 3 – 41). Thirteen infants had ileal disease, 3 ileocolic and 2 colonic disease alone. We made comparison with resected specimens from 13 infants (median age 4 days, range 1-60) who required resection for non-inflammatory indications (6 small bowel atresia, 4 perforation, 2 small bowel infarction and 1 volvulus). Immunohistochemical staining and histochemistry was performed for CD 3 T cells, HLA-DR, proliferating cells (Ki 67), heparan sulphate proteoglycan, GAGs, and neural and glial markers such as glial fibrillary acidic protein, nerve growth factor receptor, neural fibrillary protein, neuron specific enolase, as well as the cytokines IL -12 & TGF-b.

Results: In all cases with NEC, even at apparently normal resection margins, there was a dense infiltrate of HLA-DR+ macrophages expressing Ki67 in the serosa. The vascular endothelium was strongly DR+ in the submucosa and serosa. There was dense aggregation of DR+, IL -12 + cells within the lamina propria in the affected mucosa, with increased epithelial TGF-b. In 17/18 cases there was marked abnormalities of the myenteric plexus. In many cases there was perineural aggregation of CD3+ T cells. There was a strong upregulation of HLA-DR on microglial cell bodies, together with expression of IL-12 and TGF-b, which is not seen in the controls. Axonal degeneration was also seen in most, but not all, cases.

Conclusions: Our data suggest that neonatal NEC is not simply a mucosal lesion, which then extends more deeply to cause perforation. Subjacent to even apparently normal mucosa there is infiltration of proliferating macrophages from activated serosal vessels. In particular, there is evidence of abnormality of the myenteric plexus and activation of microglial cells. This may induce the dysmotility, which contributes to the development of NEC.

References
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2. Cornet A et al. Proc Natl acad Sci USA 2001; 98: 13306-13311