Role of LPS/CD14/TLR4-mediated inflammation in necrotizing enterocolitis: Pathogenesis and therapeutic implications
Chan, K.L. Wong, K.F. Luk, J.M.
Chan, K.L.
Wong, K.F.
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Abstract
AIM: To establish the roles of lipopolysaccharide (LPS)/CD14/toll-like receptor 4 (TLR4)-mediated inflammation in a rat model of human necrotizing enterocolitis (NEC). METHODS: Six pairs of intestinal samples from human NEC were collected before and after recovery for histological and molecular analysis of inflammatory cytokines and signaling components. In the rat NEC model, we isolated 10-cm jejunum segments and divided them into six groups (n = 6) for sham operation, treatment with LPS, bowel distension, combined bowel distension and LPS stimulation, and two therapeutic groups. The potential efficacy of a recombinant CD18 peptide and a monoclonal CD14 antibody was evaluated in the latter two groups. The serum and tissue levels of several inflammatory mediators were quantified by real-time polymerase chain reaction, ELISA and immunoblotting. RESULTS: Human acute phase NEC tissues displayed significant increases (P < 0.05) in levels of TLR4, CD14, myeloid differentiation protein (MD)-2, tumor necrosis factor (TNF)-α and nuclear factor-κB when compared to those after recovery. The histological and inflammatory picture of human NEC was reproduced in rats that were treated with combined bowel distension and LPS, but not in the sham-operated and other control rats. Serum levels of interleukin-6 and TNF-α were also elevated. The NEC pathology was attenuated by treating the NEC rats with a monoclonal CD14 antibody or an LPS-neutralizing peptide. CONCLUSION: LPS and distension are required to produce the histological and inflammatory features of NEC. A potential treatment option is blocking LPS activation and leukocyte infiltration. © 2009 The WJG Press and Baishideng. All rights reserved.
Keywords
CD14 antigen, Lipopolysaccharide, Necrotizing enterocolitis, Pathogenesis, Therapy, Toll-like receptor 4
Source Title
World Journal of Gastroenterology
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Date
2009
DOI
10.3748/wjg.15.4745
Type
Article