Poster Presentation Lorne Infection and Immunity 2013

Necrotising enterocolitis – a review of an evolving paradigm. (#111)

Steven SC Cho 1 , Philip J Berger 1 , Ina Rudloff 1 , Wei Cheng 1 2 , Claudia A Nold-Petry 1 , Marcel F Nold 1 3
  1. The Ritchie Centre, Monash Institute of Medical Research, Monash University, Melbourne, VIC, Australia
  2. Department of Paediatric Surgery, Monash Children’s, Southern Health. Department of Paediatrics, Department of Surgery, Southern Medical School, Faculty of Medicine, Nursing of Health Sciences, Monash University, Melbourne, VIC, Australia
  3. Monash Newborn, Monash Children´s, Southern Health, Melbourne, VIC, Australia

Necrotising enterocolitis (NEC) is a common, often severe and not rarely fatal gastrointestinal disease in preterm neonates. Although risk factors for NEC have been identified (comprising prematurity, enteral feeding, formula feeding, abnormal microbial colonisation and hypoxic-ischemic states), the pathophysiology of NEC remains largely elusive. Historically, NEC was thought to be initiated by an early postnatal ischemia-reperfusion event that disrupted intestinal barrier integrity and led to injury and inflammation. However, consistent with abnormal bacterial colonisation being a known risk factor for NEC, modern epidemiological observations have strongly correlated NEC diagnosis to coincide with the timing of bacterial colonisation of the gut. Nonetheless, clinicians and researchers have been unable to establish a causative link between NEC and a specific pathogen. This has led to the development of the current theory, by which dysregulation of the inflammatory response is blamed as the major culprit in the initiation and perpetuation of NEC. Recently, a number of studies have explored and significantly advanced our understanding of pathogenic mechanisms by revealing the pivotal role of innate immunity; particularly the pro-inflammatory TLR4 cascade has emerged as a major player. In addition, pathways not previously considered important in NEC were shown to play a role and to be interlinked with TLR4 signalling in NEC; these include PI3K/Akt-mediated enterocyte proliferation, microRNA (miR)155- and (miR)146a-mediated regulation of TLR4 signalling as well as the recent discovery of TLR4 on Lgr5+ intestinal stem cells. Here, we review the rapidly evolving field of inflammation in NEC and, in an outlook on experiments that we have recently commenced, propose an anti-inflammatory strategy against this devastating, currently untreatable disease: We aim to block the inflammatory cascade in a murine model of NEC with the powerful anti-inflammatory cytokine IL-37 whose beneficial activities we have recently described.