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Published ahead of print on September 13, 2007, doi:10.1165/rcmb.2007-0053OC

Am. J. Respir. Cell Mol. Biol., Volume 38, Number 2, February 2008, 218-226

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Submitted on February 16, 2007
Revised on September 13, 2007

Cigarette Smoke Exposure Attenuates Cytokine Production by Mouse Alveolar Macrophages

Gordon J Gaschler1, Caleb C.J. Zavitz1, Carla M.T. Bauer1, Marko Skrtic1, Maria Lindahl2, Clinton S Robbins1, Biao Chen1, and Martin R Stampfli3*

1 Department of Pathology and Molecular Medicine, McMaster University, Centre for Gene Therapeutics, Hamilton, Ontario, Canada, 2 AstraZeneca, Lund, Sweden, 3 Department of Pathology and Molecular Medicine, McMaster University, Centre for Gene Therapeutics, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada

* To whom correspondence should be addressed. E-mail: stampfli{at}mcmaster.ca.

Alveolar macrophages (aM{phi}s) play a central role in respiratory host defense by sensing microbial antigens and initiating immune-inflammatory responses early in the course of an infection. The purpose of this study was to investigate the effect of cigarette smoke exposure on aM{phi}s following stimulation of innate pattern recognition receptors (PRRs) in a murine model. To accomplish this, C57Bl/6 mice were exposed for 8 weeks using two models of cigarette smoke-exposure, nose-only or whole-body exposure, and aM{phi}s isolated from the broncho-alveolar lavage. Following stimulation of aM{phi}s with pI:C, a mimic of viral replication, and bacterial cell-wall constituent LPS, aM{phi}s from cigarette smoke-exposed mice produced significantly attenuated levels of the inflammatory cytokines TNF{alpha} and IL-6, and the chemokine RANTES. This attenuation was specific to the aM{phi} compartment, and not related to changes in aM{phi} viability or expression of TLR3 or TLR4 between groups. Furthermore, aM{phi}s from smoke-exposed mice had decreased cytokine RNA as compared to aM{phi}s from sham-exposed mice. Mechanistically, this was associated with decreased nuclear translocation of the pro-inflammatory transcription factor NF{kappa}B and increased AP-1 nuclear translocation, in aM{phi}s from smoke-exposed mice. Attenuated cytokine production was reversible following smoking cessation. Cigarette smoke-exposure also attenuated TNF{alpha} production following stimulation with NOD-Like receptor agonists, showing the effect applies more broadly to other PRR pathways. Our data demonstrate that cigarette smoke-exposure attenuates aM{phi}s responses following innate stimulation, including pathways typically associated with bacterial and viral infections.




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