AJP - GI AJP: Cell Physiology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Gastrointest Liver Physiol 289: G643-G652, 2005. First published June 9, 2005; doi:10.1152/ajpgi.00067.2005
0193-1857/05 $8.00
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
289/4/G643    most recent
00067.2005v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via Web of Science (11)
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Zamora, R.
Right arrow Articles by Ford, H. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zamora, R.
Right arrow Articles by Ford, H. R.

INFLAMMATION/IMMUNITY/MEDIATORS

High-mobility group box 1 protein is an inflammatory mediator in necrotizing enterocolitis: protective effect of the macrophage deactivator semapimod

Ruben Zamora,1 Anatoli Grishin,1 Catarina Wong,1 Patricia Boyle,1 Jin Wang,1 David Hackam,1 Jeffrey S. Upperman,1 Kevin J. Tracey,2 and Henri R. Ford1

1Department of Pediatric Surgery, Children's Hospital of Pittsburgh, and Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania; and 2Laboratory of Biomedical Science, North Shore-Long Island Jewish Research Institute, Manhasset, New York

Submitted 15 February 2005 ; accepted in final form 6 June 2005

High-mobility group box 1 (HMGB1) is a late mediator of endotoxemia known to stimulate the production of proinflammatory cytokines that are putative mediators of intestinal inflammation associated with necrotizing enterocolitis (NEC). We hypothesized that HMGB1 is also involved in the pathogenesis of NEC. We examined the expression of HMGB1 and the effect of the novel drug semapimod on intestinal inflammation in an experimental model of NEC in neonatal rats. Newborn rats were subjected to hypoxia and fed a conventional formula by gavage (FFH) or were breast fed (BF). Rats were killed on day 4, and the distal ileum was harvested for morphological studies and Western blot analysis. FFH newborn rats but not BF controls developed intestinal inflammation similar to the histological changes observed in human NEC. We found that the expression of HMGB1 and its receptor for advanced glycation end products (RAGE) as well as that of other apoptosis/inflammation-related proteins (Bad, Bax, inducible nitric oxide synthase, and cyclooxygenase 2) was upregulated in the ileal mucosa of FFH newborn rats compared with BF animals. Administration of the drug semapimod inhibited the upregulation of those proteins and partially protected the animals against the FFH-induced intestinal injury. Elevated levels of HMGB1 were also found in ileal samples from infants undergoing intestinal resection for acute NEC. Our results implicate HMGB1 and RAGE as important mediators of enterocyte cell death and hypoxia-induced injury in NEC and support the hypothesis that inhibitors such as semapimod might play a therapeutic role in chronic intestinal inflammation characterized by this animal model.

gut inflammation; hypoxia; CNI-1493; newborn rats


Address for reprint requests and other correspondence: R. Zamora, Dept. of Surgery, Univ. of Pittsburgh, W1540 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15213 (e-mail: zamorar{at}pitt.edu)






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2005 by the American Physiological Society.