The role of gender and secreted phosphoprotein 1 in early neutrophil recruitment after silica exposure in mice

Occupational exposure to silica remains a major public health problem in both the US and other industrialized nations. We previously showed that silica-exposed female mice recruit greater numbers of inflammatory cells, express less secreted phosphoprotein 1 (SPP1) and are protected against the development of silica-induced pulmonary fibrosis (PF) compared to males at 14 days post-treatment. We therefore hypothesize that estrogen supplementation will protect male mice against silica-induced PF. Inflammation is implicated in the early pathogenesis of silicosis and animal models of silica-induced pulmonary fibrosis. In addition, intercellular adhesion molecule 1(ICAM-1), an important receptor in neutrophil recruitment, is induced after 24 h, and neutrophils are the predominant inflammatory cell type recruited into the lungs after 3 days of silica exposure in mice, before any overt fibrosis is observed. The roles of gender and SPP1 in silica-induced neutrophil recruitment at pre-fibrotic time points are unknown. We further hypothesize that female mice recruit greater numbers of neutrophils at pre-fibrotic time points, and that SPP1 regulation of ICAM-1 mediates gender-specific differences in neutrophil recruitment to the lungs following exposure to crystalline silica. We show here that estrogen-treated male mice recruit greater numbers of inflammatory cells, which are predominantly macrophages, express lower levels of SPP1, and are partially protected against the development of silica-induced PF. We also show that silica-exposed female mice recruit greater numbers of neutrophils, have more extensive tissue injury and express less SPP1 and more ICAM-1 mRNA compared to exposed males at 3 days post-treatment. Interestingly, SPP1 deficiency does not influence neutrophil recruitment and lung tissue injury and upregulates ICAM-1 mRNA expression at 3 days post-silica exposure. We therefore suggest that the estrogen-mediated regulation of SPP1 may play a role in the gender-specific differences in silica-induced PF in mice. In addition, SPP1-mediated regulation of ICAM-1 does not account for the gender-specific differences in neutrophil recruitment into the lungs at pre-fibrotic time points. This study broadens the knowledge of silicosis, may provide insight into possible therapeutic measures to slow the progression of or cure silicosis and contributes to public health strategies and reduces the global burden of silicosis