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1 Department of Medicine, University of Rochester, Rochester, NY, USA
2 Schering Plough Research Institute, Kenilworth, NJ, USA
3 Department of Environmental Medicine and the Lung Biology and Disease Program, University of Rochester, Rochester, NY, USA
4 Department of Medicine, University of Rochester, Rochester, NY, USA; Department of Environmental Medicine and the Lung Biology and Disease Program, University of Rochester, Rochester, NY, USA
* To whom correspondence should be addressed. E-mail: richard_phipps{at}urmc.rochester.edu.
It has been hypothesized that the destruction of lung tissue observed in smokers with chronic obstructive pulmonary disease and emphysema is mediated by neutrophils recruited to the lungs by smoke exposure. This study investigated the role of the chemokine receptor CXCR2 in mediating neutrophilic inflammation in the lungs of mice acutely exposed to cigarette smoke. Exposure to dilute mainstream cigarette smoke for 1 hour, twice per day for 3 days induced acute inflammation in the lungs of C57BL/6 mice, with increased neutrophils and neutrophil chemotactic CXC chemokines MIP-2 and KC. Treatment with SCH-N, an orally active small molecule inhibitor of CXCR2, reduced the influx of neutrophils into the bronchoalveolar lavage (BAL) fluid. Histologic changes were seen, with drug treatment reducing perivascular inflammation and the number of tissue neutrophils. 
-glucuronidase activity was reduced in the BAL fluid of mice treated with SCH-N, indicating that the reduction in neutrophils was associated with a reduction in tissue damaging enzymes. Interestingly, while MIP-2 and KC were significantly elevated in the BAL fluid of smoke exposed mice, they were further elevated in mice exposed to smoke and treated with drug. The increase in MIP-2 and KC with drug treatment may be due to the decrease in lung neutrophils which either are not present to bind these chemokines or which fail to provide a feedback signal to other cells that produce these chemokines. Overall, these results demonstrate that inhibiting CXCR2 reduces neutrophilic inflammation and associated lung tissue damage due to acute cigarette smoke exposure.
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