Abstract
BackgroundOccupational and environmental exposure to crystalline silica may lead to the development of silicosis, which is characterized by inflammation and progressive fibrosis. A substantial number of patients diagnosed with silicosis develop pulmonary hypertension. Pulmonary hypertension associated with silicosis and with related restrictive lung diseases significantly reduces survival in affected subjects. An animal model of silicosis has been described previously however, the magnitude of vascular remodeling and hemodynamic effects of inhaled silica are largely unknown. Considering the importance of such information, this study investigated whether mice exposed to silica develop pulmonary hypertension and vascular remodeling.MethodsC57BL6 mice were intratracheally injected with either saline or crystalline silica at doses 0.2 g/kg, 0.3 g/kg and 0.4 g/kg and then studied at day 28 post-exposure. Pulmonary hypertension was characterized by changes in right ventricular systolic pressure and lung histopathology.ResultsMice exposed to saline showed normal lung histology and hemodynamic parameters while mice exposed to silica showed increased right ventricular systolic pressure and marked lung pathology characterized by a granulomatous inflammatory reaction and increased collagen deposition. Silica-exposed mice also showed signs of vascular remodeling with pulmonary artery muscularization, vascular occlusion, and medial thickening. The expression of pro-inflammatory genes such as TNF-α and MCP-1 was significantly upregulated as well as the expression of the pro-remodeling genes collagen type I, fibronectin and the metalloproteinases MMP-2 and TIMP-1. On the other hand, the expression of several vasculature specific genes involved in the regulation of endothelial function was significantly attenuated.ConclusionsWe characterized a new animal model of pulmonary hypertension secondary to pulmonary fibrosis induced by crystalline silica. Our data suggest that silica promotes the damage of the pulmonary vasculature through mechanisms that might involve endothelial dysfunction, inflammation, and vascular remodeling.
Highlights
Occupational and environmental exposure to crystalline silica may lead to the development of silicosis, which is characterized by inflammation and progressive fibrosis
With a silica dose of 0.4 g/kg, mice lost up to 16% of their body weight, but regained close to the weight of the control group by day 14. This quick recovery of body weight is in contrast with our observations after bleomycin treatment where weight loss was more severe and maximum body weight loss was observed around day 10
Silica-induced lung fibrosis To confirm the effects of silica instillation on the pathogenesis of lung inflammation and fibrosis, the lung tissues of mice were observed using light microscopy to monitor pathological changes
Summary
Occupational and environmental exposure to crystalline silica may lead to the development of silicosis, which is characterized by inflammation and progressive fibrosis. The exact mechanisms responsible for these changes remain unclear, it is well established that inhaled silica particles are engulfed by macrophages, which leads to cell activation and death followed by the release of intracellular silica that is taken up by other macrophages. This recurring cycle of cell death and macrophage activation produces the influx of inflammatory cells and the production of cytokines and reactive oxygen and nitrogen species [8]. Cardiovascular diseases are among the leading causes of death in patients with silicosis [11]
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