A Biphasic Response to Silica

Abstract

Inhalation of crystalline silica may lead to acute or chronic silicosis. Although chronic silicosis is associated with increased incidence/exacerbation of autoimmune disorders, the immunologic effects of chronic silicosis are not completely understood. In an animal model of chronic silicosis, Lewis rats were exposed to filtered air or silica (1.75 microm average particle size) at an exposure concentration of 6.2 mg/m(3), 6 h/d, 5 d/wk for 6 wk, and observed up to 27 wk after the exposure. Based on silica burden, lung histopathology, and immunologic changes, two distinct stages were identified in the development of chronic silicosis. Stage 1 (4-28 d after exposure) was characterized by silica deposition in various tissues, and augmented antibody and cellular immunity. Although bronchoalveolar lavage contained an increased number of activated macrophages, protein and lactate dehydrogenase levels were comparable to controls. In Stage 2 (>/= 10 wk), silica was localized in epithelioid macrophages, and T cell immunity had returned to normal, but the lavage fluids contained increased protein concentration and lactate dehydrogenase activity. Moreover, lungs from silica-treated animals contained neutrophils and lymphocytes, and exhibited granulomatous changes around the silica-containing epithelioid macrophages. Thus, in the early stages of silicosis, silica activates the immune system; however, the progression of lung granulomas does not depend on a continually activated adaptive immune system.

Fibrogenic and Redox-Related but not Proinflammatory Genes are Upregulated in Lewis Rat Model of Chronic Silicosis

“…Silica exposure level of these animals was within the range of human occupational exposure (Hnizdo and Sluis-Cremer 1993). As previously described, other than an increased number of foamy (e.g., silica-containing) macrophages, there were no apparent signs of lung inflammation between 4 and 28 day post-silica exposure (Langley et al 2004). Animals were sacrificed at 4 day, or 7, 14 and 28 weeks after the last silica exposure (Langley et al 2010).…”

“…Rats were sub-chronically exposed to silica by inhalation as described (Langley et al 2004). Briefly, exposure chambers were maintained with an airflow rate of approximately 15 cubic feet /m and temperature range of 22–26°C.…”

“…Briefly, exposure chambers were maintained with an airflow rate of approximately 15 cubic feet /m and temperature range of 22–26°C. Animals were exposed to 6.2 mg/m 3 aerosolized silica (Min-U-Sil 5; U.S. Silica, Mill Creek, OK) with an average particle size of 1.75 ± 0.05 µm (mass median aerodynamic diameter) 6 hr/day, 5 days/week (Monday–Friday) for 6 weeks (Langley et al 2004). Control animals received filtered air under similar inhalation conditions.…”

“…Chronic silicosis is generally associated with occupational exposure to crystalline silica and mainly prevalent in stone dressers, miners, and quarry and foundry workers (Shi et al 1998; Hnizdo and Sluis-Cremer 1993; Chong et al 2006). Although in animals, both high-dose acute and low-dose chronic silica exposures induce granulomatous changes in the lung (Borges et al 2002; Langley et al 2004; 2010; Castranova et al 2002), the granuloma-like structures in acute silicosis are loosely aggregated foamy histiocytes and lymphocytes. On the other hand, chronic silicotic granulomas in humans (Hnizdo and Vallyathan 2003) and animals (Langley et al 2004; 2010) are small, well-organized nodules consisting of epithelioid macrophages and multinucleated giant cells (MGC), and generally, in humans arise after decades of asymptomatic latency (Chong et al 2006).…”

“…Although in animals, both high-dose acute and low-dose chronic silica exposures induce granulomatous changes in the lung (Borges et al 2002; Langley et al 2004; 2010; Castranova et al 2002), the granuloma-like structures in acute silicosis are loosely aggregated foamy histiocytes and lymphocytes. On the other hand, chronic silicotic granulomas in humans (Hnizdo and Vallyathan 2003) and animals (Langley et al 2004; 2010) are small, well-organized nodules consisting of epithelioid macrophages and multinucleated giant cells (MGC), and generally, in humans arise after decades of asymptomatic latency (Chong et al 2006). Silicosis is a progressive disease that is resistant to all treatment, including corticosteroid therapy (Chong et al 2006).…”