Tumor necrosis factor-α mediates hyperglycemia-augmented... : Critical Care Medicine (original) (raw)

Laboratory Investigations

Tumor necrosis factor-α mediates hyperglycemia-augmented gut barrier dysfunction in endotoxemia*

Yajima, Satoshi MD; Morisaki, Hiroshi MD; Serita, Ryohei MD; Suzuki, Takeshi MD; Katori, Nobuyuki MD; Asahara, Takashi PhD; Nomoto, Koji PhD; Kobayashi, Fujio BA; Ishizaka, Akitoshi MD; Takeda, Junzo MD

From the Departments of Anesthesiology (SY, RS, TS, NK, HM, JT), and Medicine (AI), Keio University School of Medicine, Tokyo, Japan; Yakult Central Institute for Microbiological Research (TA, KN), Tokyo, Japan; Research & Development Division (FK), Tanabe-Mitsubishi Pharma Corporation, Yokohama, Japan.

Supported by funds from Keio Medical Research Funds and Yakult Bioscience Foundation.

The authors have not disclosed any potential conflicts of interest.

For information regarding this article, E-mail: [email protected]

Abstract

Objective:

To examine whether hyperglycemia would augment gut barrier dysfunction and inflammatory responses in endotoxemic rats, and simultaneously to clarify the roles of tumor necrosis factor (TNF)-α in alterations of gut mucosal permeability associated with hyperglycemia.

Design:

Prospective randomized animal study.

Setting:

University research laboratory.

Subjects:

Male Wistar rats treated with lipopolysaccharide (LPS) injection.

Interventions:

After LPS injection (4 mg/kg), rats were randomly allocated into group S (n = 6), group G (n = 7), or group GI (n = 8) with continuous infusion of different fluid solutions: normal saline, 40% glucose or 10% glucose mixed with insulin, respectively. Blood glucose, insulin, and proinflammatory cytokines, accompanied by gut mucosal permeability using an in situ loop preparation of gut with fluorescence isothiocyanate-conjugated dextran, were measured. Bacterial growth or alterations in mesenteric lymph nodes and cecal contents were also assessed. We further determined the roles of TNF-α using an inhibitor of TNF-α converting enzyme in gut barrier dysfunction under the same experimental settings.

Measurements and Main Results:

Hyperglycemia over 400 mg/dL was achieved and kept in group G during the study period whereas normoglycemia was preserved in group S and GI, the latter of which showed the similar extent of hyperinsulinemia to group G. Plasma concentrations of fluorescence-labeled dextran and TNF-α in group G were significantly higher vs. group S and GI, and the number of bacteria found in mesenteric lymph nodes in group G was greater compared with group S. Intestinal environments including microflora and organic acids were not altered by blood glucose or insulin level. Inhibiting conversion of membrane-bound to soluble type of TNF-α restored gut mucosal permeability augmented by hyperglycemia.

Conclusions:

These findings indicate that hyperglycemia deteriorates LPS-elicited gut barrier dysfunction and bacterial translocation independently of plasma insulin level, and that TNF-α mediates such mucosal dysfunction of gut in endotoxemia.