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Environ Health Perspect; DOI:10.1289/ehp.1510335

Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice

Joseph D. Latoche1*, Alexander Chukwuma Ufelle1*, Fabrizio Fazzi1, Koustav Ganguly1,2, George D. Leikauf1, and Cheryl L. Fattman1
Author Affiliations open
1Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA; 2SRM Research Institute, SRM University, Chennai 603203, India

*These authors contributed equally to this work

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  • Background: Fibrotic lung diseases occur predominantly in males and reports describe better survival in affected females. Male mice are more sensitive to silica-induced lung fibrosis compared to silica-treated female mice. Secreted phosphoprotein 1 (SPP1, aka osteopontin) increases in pulmonary fibrosis, and SPP1 transcription may be regulated by estrogen or estrogen receptor-related receptors.

    Objective: To determine whether differences in silica-induced SPP1 expression contributes to sex differences in lung fibrosis.

    Methods: Male and female mice were treated with 0.2g/kg intratracheal silica and lung injury was assessed 1, 3, or 14 days post-exposure. Gene-targeted (Spp1-/-) mice, control Spp1+/+ (C57BL/6J) mice, ovariectomized (OVX) female mice, or estrogen-treated male mice were treated with silica and lung injury was assessed.

    Results: Silica-induced SPP1 in lung tissue, bronchoalveolar lavage, and serum increased more in male than female mice. Following silica treatment, bronchoalveolar lavage cell infiltrates decreased in female Spp1-/- mice compared to female Spp 1+/+ mice, and lung hydroxyproline decreased in male Spp1-/- mice compared to male Spp1+/+ mice. OVX female mice had increased lung SPP1 expression in response to silica compared to silica-treated sham female mice. Silica-induced lung collagen and hydroxyproline (markers of fibrosis), and SPP1 expression decreased in estrogen treated males compared to untreated males.

    Conclusion: These findings suggest that sex-specific differences in SPP1 expression contribute to the differential sensitivity of male and female mice to the development of silica-induced fibrosis.

  • This EHP Advance Publication article has been peer-reviewed, revised, and accepted for publication. EHP Advance Publication articles are completely citable using the DOI number assigned to the article. This document will be replaced with the copyedited and formatted version as soon as it is available. Through the DOI number used in the citation, you will be able to access this document at each stage of the publication process.

    Citation: Latoche JD, Ufelle AC, Fazzi F, Ganguly K, Leikauf GD, Fattman CL. Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice. Environ Health Perspect;

    Received: 12 June 2015
    Accepted: 22 February 2016
    Advance Publication: 8 March 2016

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