Academic journal article Environmental Health Perspectives

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

Academic journal article Environmental Health Perspectives

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

Article excerpt

Introduction

A chronic fibrotic lung disease caused by silica inhalation, silicosis is a detrimental occupational disease, with thousands of new cases being reported worldwide every year (Leung et al. 2012). Hazardous occupational exposures occur in mining, sandblasting, road construction, pottery making, masonry, and tunneling operations. Recently, silica exposures have occurred during hydraulic fracturing of gas and oil wells (Esswein et al. 2013) and during the fabrication and installation of engineered stone countertops (Kramer et al. 2012). Nonoccupational silica exposures can result near industrial and nonindustrial sources (Bhagia 2012). In the United States, age-adjusted mortality rates have dropped from 8.9 per 1,000,000 in 1968 to 0.4 per 1,000,000 in 2010 (Bang et al. 2015). In recent years, silicosis has increased along with increased coal workers' pneumoconiosis (Halldin et al. 2015; Laney and Weissman 2014) and patients are younger and develop accelerated, severe silicosis with higher mortality (Laney and Weissman 2014).

Most silicosis patients are men because occupations associated with silicosis have been historically male-dominated (Leung et al. 2012), and limited data suggest that survival may be better in women (Morozova 2012). Similarly, other fibrotic lung diseases (e.g., idiopathic pulmonary fibrosis) also occur predominantly in men (Raghu et al. 2006), and women experience better survival (Gribbin et al. 2006; Han et al. 2008; McCormack et al. 1995; Raghu et al. 2014; Schwartz et al. 1994). This discrepancy suggests that sex can influence pulmonary fibrosis pathogenesis. However, the manner in which sex alters the development and progression of pulmonary fibrosis is largely unknown, inasmuch because most studies control for sex rather than examine sex-specific effects. Furthermore, animal studies fail to clearly define the relationship between sex and pulmonary fibrosis (Carey et al. 2007). For example, female rats develop more severe bleomycin-induced pulmonary fibrosis than male rats (Gharaee-Kermani et al. 2005), whereas male mice develop more severe bleomycin-induced pulmonary fibrosis than female mice (Redente et al. 2011; Voltz et al. 2008).

Secreted phosphoprotein-1 (SPP1) is an extracellular matrix protein and cytokine associated with inflammatory and profibrotic effects in a number of organs (Wang and Denhardt 2008). In the lung, macrophages, lymphocytes, and alveolar epithelial cells produce SPP1 (Ganguly et al. 2014; O'Regan 2003). As a pleiotropic cytokine, SPP1 stimulates macrophage and neutrophil chemotaxis, type-1 cytokine secretion, and macrophage and lymphocyte differentiation (Lund et al. 2009; Wang and Denhardt 2008). As a pro-fibrotic molecule, SPP1 controls the expression and augments the effects of other profibrotic mediators, such as transforming growth factor beta 1 (TGFB1), on fibroblast proliferation and myofibroblastic differentiation (Nagao et al. 2012; Xiao et al. 2012). SPP1 also mediates fibroblast migration through integrin- (Anwar et al. 2012; Li et al. 2000) and matrix metalloproteinase-dependent mechanisms (Lund et al. 2009). Lung SPP1 increases in humans with pulmonary fibrosis (Foster et al. 2015; Nau et al. 1997; Pardo et al. 2005) and in mouse (Berman et al. 2004; Miyazaki et al. 1995; Oh et al. 2015; Sabo-Attwood et al. 2011; Takahashi et al. 2001) and rat (Langley et al. 2011; Ma et al. 2012; Mangum et al. 2004) models of pulmonary fibrosis. In addition, SPP1 may be a useful biomarker for the development and progression of fibrotic lung diseases (Boon et al. 2009; Kadota et al. 2005; Kelly et al. 2006; O'Regan et al. 2006; Pardo et al. 2005; Selman et al. 2006; Vij and Noth 2012). Gene-targeted [Spp1.sup.-/-] mice developed less bleomycin-induced pulmonary fibrosis (Berman et al. 2004) as well as reduced injury in models of renal, heart, kidney, and liver fibrosis (Rittling and Denhardt 1999).

Previously, we observed that silica-treated male mice develop more fibrosis but show a weaker inflammatory response than silica-treated female mice (Brass et al. …

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