Published ahead of print on November 22, 2006, doi:10.1165/rcmb.2006-0038OC Am. J. Respir. Cell Mol. Biol., Volume 36, Number 4, April 2007, 504-512 A more recent version of this article appeared on April 1, 2007
Submitted on January 26, 2006 Impact of IL-10 on Diaphragmatic Cytokine Expression and Contractility During Pseudomonas InfectionMaziar Divangahi1,1 Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre, Montreal, Quebec, Canada, 2 Meakins-Christie Laboratories and Respiratory Division, McGill University Health Centre, Montreal, Quebec, Canada; UPRES EA2397, Universite Paris 6 Pierre et Marie Curie, Paris, France, 3 Centre for Gene Therapeutics, McMaster University, Hamilton, Ontario, Canada * To whom correspondence should be addressed. E-mail: basil.petrof{at}mcgill.ca.
Severe weakness of the respiratory muscles, with attendant respiratory failure and death, has been documented in sepsis. In this study, we show that during murine pulmonary infection with Pseudomonas aeruginosa, multiple pro-inflammatory genes are upregulated not only within the lungs, but also within the diaphragm. Significant induction of TNF-
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, IL-1
, IL-6 and IL-18 gene expression occurred within the diaphragm in a bacterial dose-dependent manner. We determined whether the anti-inflammatory cytokine IL-10 could blunt pro-inflammatory gene expression within the diaphragm under these conditions. The IL-10 receptor was found to be expressed by the diaphragm in vivo as well as in primary diaphragmatic muscle cell cultures. Transduction of myoblasts with an adenoviral vector (Ad-IL-10) induced strong IL-10 expression, and intramuscular injection of the same vector in vivo produced significant increases in IL-10 serum levels. Ad-IL-10 treatment of mice infected with P. aeruginosa significantly inhibited the induction of pro-inflammatory cytokines within the diaphragm, but not in the infected lungs. Ad-IL-10 treatment also led to greatly improved diaphragmatic force production in infected mice. These results suggest that pulmonary infection triggers pro-inflammatory gene expression by the diaphragm along with diaphragmatic weakness. Shifting the balance between pro- and anti-inflammatory mediators in favor of the latter by IL-10 gene delivery was able to restore normal diaphragmatic force-generating capacity under these conditions, suggesting a possible avenue for therapeutic intervention.
