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

Ruben Zamora, Anatoli Grishin, Catarina Wong, Patricia Boyle, Jin Wang, David Hackam, Jeffrey S. Upperman, Kevin J. Tracey, Henri Ford

Research output: Contribution to journalArticle

39 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Volume289
Issue number4 52-4
DOIs
StatePublished - Oct 1 2005
Externally publishedYes

Fingerprint

HMGB1 Protein
Necrotizing Enterocolitis
Macrophages
Inflammation
Breast
bcl-Associated Death Protein
Cell Hypoxia
bcl-2-Associated X Protein
Inflammation Mediators
Endotoxemia
Enterocytes
Wounds and Injuries
Nitric Oxide Synthase Type II
Cyclooxygenase 2
Ileum
Pharmaceutical Preparations
semapimod
Mucous Membrane
Cell Death
Theoretical Models

Keywords

  • CNI-1493
  • Gut inflammation
  • Hypoxia
  • Newborn rats

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

High-mobility group box 1 protein is an inflammatory mediator in necrotizing enterocolitis : Protective effect of the macrophage deactivator semapimod. / Zamora, Ruben; Grishin, Anatoli; Wong, Catarina; Boyle, Patricia; Wang, Jin; Hackam, David; Upperman, Jeffrey S.; Tracey, Kevin J.; Ford, Henri.

In: American Journal of Physiology - Gastrointestinal and Liver Physiology, Vol. 289, No. 4 52-4, 01.10.2005.

Research output: Contribution to journalArticle

Zamora, Ruben ; Grishin, Anatoli ; Wong, Catarina ; Boyle, Patricia ; Wang, Jin ; Hackam, David ; Upperman, Jeffrey S. ; Tracey, Kevin J. ; Ford, Henri. / High-mobility group box 1 protein is an inflammatory mediator in necrotizing enterocolitis : Protective effect of the macrophage deactivator semapimod. In: American Journal of Physiology - Gastrointestinal and Liver Physiology. 2005 ; Vol. 289, No. 4 52-4.
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