title: Secreted Phosphoprotein 1 and Sex-Specific Differences in Silica-Induced Pulmonary Fibrosis in Mice.
abstract: 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 than silica-treated female mice. Secreted phosphoprotein 1 (SPP1, also known as osteopontin) increases in pulmonary fibrosis, and Spp1 transcription may be regulated by estrogen or estrogen receptor-related receptors.
  
  
  
  We determined whether differences in silica-induced SPP1 levels contribute to sex differences in lung fibrosis.
  
  
  
  Male and female mice were treated with 0.2 g/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, and estrogen-treated male mice were treated with silica, and lung injury was assessed.
  
  
  
  Silica-induced SPP1 in lung tissue, bronchoalveolar lavage, and serum increased more in male than in female mice. Following silica treatment, bronchoalveolar lavage cell infiltrates decreased in female Spp1-/- mice compared with female Spp1+/+ mice, and lung hydroxyproline decreased in male Spp1-/- mice compared with male Spp1+/+ mice. OVX female mice had increased lung SPP1 expression in response to silica compared with silica-treated sham female mice. Silica-induced lung collagen and hydroxyproline (markers of fibrosis), and SPP1 levels decreased in estrogen-treated males compared with untreated males.
  
  
  
  These findings suggest that sex-specific differences in SPP1 levels contribute to the differential sensitivity of male and female mice to the development of silica-induced fibrosis.
  
  
  
  Latoche JD, Ufelle AC, Fazzi F, Ganguly K, Leikauf GD, Fattman CL. 2016. Secreted phosphoprotein 1 and sex-specific differences in silica-induced pulmonary fibrosis in mice. Environ Health Perspect 124:1199-1207; http://dx.doi.org/10.1289/ehp.1510335.
authors.affiliation: Department of Environmental and Occupational Health, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Latoche
authors.forename: Alexander Chukwuma
authors.initials: AC
authors.lastname: Ufelle
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Fazzi
authors.forename: Koustav
authors.initials: K
authors.lastname: Ganguly
authors.forename: George D
authors.initials: GD
authors.lastname: Leikauf
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Fattman
mesh_terms: D000393:Air Pollutants / Q000633:toxicity*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid; D005260:Female; D019570:Inhalation Exposure / Q000032:analysis*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D053495:Osteopontin / Q000378:metabolism*; D012737:Sex Factors; D012822:Silicon Dioxide / Q000633:toxicity*
chemical_list: D000393:Air Pollutants; C506896:Spp1 protein, mouse; D053495:Osteopontin; D012822:Silicon Dioxide