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Male Sex Hormones Exacerbate Lung Function Impairment after Bleomycin-Induced Pulmonary Fibrosis

¹ Division of Intramural Research, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina; and ² Department of Environmental and Molecular Toxicology, North Carolina State University, Raleigh, North Carolina

Correspondence and requests for reprints should be addressed to Darryl C. Zeldin, M.D., NIH/NIEHS, 111 T.W. Alexander Drive, Building 101, Room D236, Research Triangle Park, NC 27709. E-mail: zeldin{at}niehs.nih.gov

The roles of sex hormones as modulators of lung function and disease have received significant attention as differential sex responses to various lung insults have been recently reported. The present study used a bleomycin-induced pulmonary fibrosis model in C57BL/6 mice to examine potential sex differences in physiological and pathological outcomes. Endpoints measured included invasive lung function assessment, immunological response, lung collagen deposition, and a quantitative histological analysis of pulmonary fibrosis. Male mice had significantly higher basal static lung compliance than female mice (P < 0.05) and a more pronounced decline in static compliance after bleomycin administration when expressed as overall change or percentage of baseline change (P < 0.05). In contrast, there were no significant differences between the sexes in immune cell infiltration into the lung or in total lung collagen content after bleomycin. Total lung histopathology scores measured using the Ashcroft method did not differ between the sexes, while a quantitative histopathology scoring system designed to determine where within the lung the fibrosis occurred indicated a tendency toward more fibrosis immediately adjacent to airways in bleomycin-treated male versus female mice. Furthermore, castrated male mice exhibited a female-like response to bleomycin while female mice given exogenous androgen exhibited a male-like response. These data indicate that androgens play an exacerbating role in decreased lung function after bleomycin administration, and traditional measures of fibrosis may miss critical differences in lung function between the sexes. Sex differences should be carefully considered when designing and interpreting experimental models of pulmonary fibrosis in mice.

Key Words: fibrosis • bleomycin • sex • respiratory mechanics

CLINICAL RELEVANCE We describe a sex discrepancy in bleomycin-induced fibrosis, and illustrate the utility of lung function as an endpoint. This will facilitate more accurate modeling of fibrosis, and will provide a physiological endpoint to assess intervention efficacy.