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Clara Cells Attenuate the Inflammatory Response through Regulation of Macrophage Behavior

¹ Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania; ² Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, Duke University Medical Center, Durham, North Carolina; ³ The Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases, Pulmonary, Allergy and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Barry R. Stripp, Ph.D., Duke University Medical Center, 2075 MSRBII, 106 Research Drive, DUMC Box 103000, Durham, NC 27710. E-mail: barry.stripp{at}duke.edu

Chronic lung diseases are marked by excessive inflammation and epithelial remodeling. Reduced Clara cell secretory function and corresponding decreases in the abundance of the major Clara cell secretory protein (CCSP) are characteristically seen in these disease states. We sought to define the impact of Clara cell and CCSP depletion on regulation of the lung inflammatory response. We used chemical and genetic mouse models of Clara cell and CCSP deficiency (CCSP^–/–) coupled with Pseudomonas aeruginosa LPS elicited inflammation. Exposure of Clara cell–depleted or CCSP^–/– mice to LPS resulted in augmented inflammation as assessed by polymorphonuclear leukocyte recruitment to the airspace. Gene expression analysis and pathway modeling of the CCSP^–/– inflammatory response implicated increased TNF- signaling. Consistent with this model was the demonstration of significantly elevated TNF- in airway fluid of LPS-stimulated CCSP^–/– mice compared with similarly exposed wild-type mice. Increased LPS-elicited TNF- production was also observed in cultured lung macrophages from CCSP^–/– mice compared with wild-type mice. We demonstrate that macrophages from Clara cell–depleted and CCSP^–/– mice displayed increased Toll-like receptor 4 surface expression. Our results provide evidence that Clara cells can attenuate inflammation through regulation of macrophage behavior, and suggest that epithelial remodeling leading to reduced Clara cell secretory function is an important factor that increases the intensity of lung inflammation in chronic lung disease.

Key Words: Clara cell • Clara cell secretory protein • inflammation • LPS • macrophage

CLINICAL RELEVANCE This study defines a new role for Clara cell secretions in regulation of innate immunity. This finding is of clinical importance, as Clara cell abundance and secretory capacity are attenuated in the setting of chronic lung diseases.