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Role of Toll-like receptor 4 for the pathogenesis of acute lung injury in Gram-negative sepsis.

Abstract：

BACKGROUND AND OBJECTIVE:Proinflammatory cytokines as well as nitric oxide (NO) play a major role in mediating the response to lipopolysaccharide (LPS). The present study tested the hypothesis that LPS induces proinflammatory cytokines in the lung via the Toll-like receptor 4 (TLR4)/CD14 signalling cascade. METHODS:Control mice and TLR4-deficient (TLR4-D) mice were used to test TLR4-mediated effects of LPS. Both strains received either Escherichia coli LPS (20 mg kg-1 intraperitoneal) or saline and their lungs were collected at different time points. Pulmonary nuclear factor kappaB (NFkappaB) activation was investigated with electromobility shift assay. mRNA expression of inflammatory mediators and their corresponding receptors were detected with Ribonuclease Protection Assay. Protein expression was detected by ELISA and western blotting. Inducible NO synthase (iNOS) expression was monitored by RT-PCR and iNOS activity by conversion of l-arginine to citrulline. Immune cells were sampled by bronchoalveolar lavage (BAL) and classified. RESULTS:LPS application induced CD14-, but not TLR4 protein expression in control mice. Activation of pulmonary NFkappaB was observed within 60 min in control, but not in TLR4-D mice. Six hours of LPS administration induced a significant increase in pulmonary tumour necrosis factor alpha-, interleukin-1beta- and interleukin-6 mRNA and protein expression in control mice compared to TLR4-D mice. Furthermore, LPS induced a significantly higher increase of the iNOS expression and catalytic activity in control mice than in TLR4-D mice. BAL revealed an increase in total cell count in all LPS treated mice. CONCLUSION:Our findings suggest that TLR4 plays a key role for regulating the expression of relevant cytokines within the lung during endotoxic shock.

journal_name

Eur J Anaesthesiol

journal_title

European journal of anaesthesiology

authors

Baumgarten G,Knuefermann P,Wrigge H,Putensen C,Stapel H,Fink K,Meyer R,Hoeft A,Grohé C

doi

10.1017/S0265021506001098

subject

Has Abstract

pub_date

2006-12-01 00:00:00

pages

1041-8

issue

eissn

0265-0215

issn

1365-2346

pii

S0265021506001098

journal_volume

pub_type

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Role of Toll-like receptor 4 for the pathogenesis of acute lung injury in Gram-negative sepsis.