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Published ahead of print on June 15, 2006, doi:10.1164/rccm.200509-1511OC

Am. J. Respir. Crit. Care Med., Volume 174, Number 6, September 2006, 646-653

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Submitted on September 27, 2005
Accepted on June 14, 2006

Endotoxin Triggers NF-{kappa}B-Dependent Upregulation of Multiple Pro-inflammatory Genes in the Diaphragm

Alexandre Demoule1, Maziar Divangahi1, Linda Yahiaoui1, Gawiyou Danialou1, Dusanka Gvozdic1, Katherine Labbe1, Weisheng Bao1, and Basil J Petrof2*

1 McGill University, Meakins-Christie Laboratories, Montreal, Quebec, Canada, 2 McGill University, Meakins-Christie Laboratories, Montreal, Quebec, Canada; Respiratory Division, McGill University Health Center, Montreal, Quebec, Canada

* To whom correspondence should be addressed. E-mail: basil.petrof{at}mcgill.ca.

Background: Sepsis-induced diaphragmatic force loss and failure are associated with an increased exposure of the muscle to pro-inflammatory mediators. Objectives: 1) Test the hypothesis that force-inhibiting mediators may arise in large part from the diaphragm itself; and 2) Evaluate the roles of mechanical stress, free radicals, and the NF-{kappa}B transcription factor pathway in endotoxin (LPS)-induced pro-inflammatory responses of the diaphragm. Methods: Murine diaphragm and limb muscle cells were exposed to LPS both in vitro and in vivo. Pro-inflammatory gene expression was measured using RNase protection assays (TNF-{alpha}, TNF-{alpha} receptor p55, IL-1{alpha}, IL-1{beta}, IL-6, MIP-2, ICAM-1, Fas-L, iNOS) and ELISAs (TNF-{alpha}, IL-6, MIP-2). Cyclical muscle cell stretch and free radical scavengers (N-acetylcysteine and catalase) were used to alter mechanical and oxidative stress levels, respectively. Pharmacological (PDTC) and dominant negative transfection strategies were employed to inhibit the NF-{kappa}B pathway. Results: In primary diaphragm muscle cell cultures, modulation of mechanical stress levels or free radical exposure did not alter responses to LPS stimulation. However, pharmacological blockade of the NF-{kappa}B pathway, as well as dominant negative molecular inhibition of IKB kinase (IKK)-{beta} (but not IKK-{alpha}), strongly suppressed LPS-induced pro-inflammatory gene expression. In vivo, acute endotoxemia induced significantly greater mRNA and protein levels for pro-inflammatory mediators in the diaphragm as compared to limb muscle, and basal expression levels of pro-inflammatory genes were also significantly higher in the diaphragm. Conclusions: Constitutive as well as LPS-induced pro-inflammatory gene expression are exaggerated in the diaphragm compared to limb muscles, and are critically dependent upon the NF-{kappa}B pathway. We suggest the diaphragm may be relatively predisposed to pro-inflammatory responses.
Key words: Respiratory muscles, diaphragm, inflammation, sepsis, LPS, cytokines, NF-{kappa}B, primary cell cultures




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