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1 Department of Pharmaceutical Sciences, Pharmacology/Toxicology Graduate Program, College of Pharmacy, Washington State University, Pullman, WA, USA
2 Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA, USA
3 Department of Biochemistry and Molecular Biology, University of Minnesota, Duluth, MN, USA
4 Department of Pharmaceutical Sciences, Pharmacology/Toxicology Graduate Program, College of Pharmacy, Washington State University, Pullman, WA, USA; Department of Veterinary Clinical Sciences, Washington State University, Pullman, WA, USA
* To whom correspondence should be addressed. E-mail: bpl{at}wsu.edu.
In contrast to the role of neutrophils in bacterial infection, less is known about their role during pulmonary viral infection. Our laboratory and others have noted that exposure to the pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) results in excess neutrophils in the lungs of mice infected with influenza A virus. TCDD is the most potent agonist for the aryl hydrocarbon receptor (AhR), and exposure to AhR ligands has been correlated with exacerbated inflammatory diseases of the lung. However, knowledge of the effects of AhR agonists on neutrophils is highly limited. Likewise, the factors that regulate neutrophil responses during respiratory viral infections are not well characterized. To address these knowledge gaps, we determined the in vivo levels of KC, MIP-1
, MIP-2, LIX, IL-6, and C5a in the lungs of infected mice. Our data show that these neutrophil chemoattractants are generally produced transiently in the lung within 12-24 hr of infection. We also report that expression of CD11a, CD11b, CD49d, CD31 and CD38 is increased on pulmonary neutrophils in response to influenza virus. Using AhR-deficient mice, we demonstrate that excess neutrophilia in the lung is mediated by activation of the AhR, and that this enhanced neutrophilia correlates directly with decreased survival in TCDD-exposed mice. While AhR activation results in more neutrophils in the lungs, we show that this is not mediated by deregulation in levels of common neutrophil chemoattractants, expression of adhesion molecules on pulmonary neutrophils, or delayed death of neutrophils. Likewise, exposure to TCDD did not enhance pulmonary neutrophil function. This study provides an important first step in elucidating the mechanisms by which AhR agonists exacerbate pulmonary inflammatory responses.
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