|Topic:||26. Physiology/Pathophysiology: Pulmonary Vascular and Right Ventricular Health and Disease / Adult / Cellular/Molecular Investigation / Pulmonary Circulation (PC)|
|Authors:||I.N. Zelko, J.X. Zhu, J.D. Ritzenthaler, J. Roman; Louisville, KY/US|
Rationale: Occupational 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.
Methods: C57BL6 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 right ventricular hypertrophy. Vascular remodeling and pulmonary fibrosis was measured after staining lungs with Mason’s trichrome or after immunohistochemical staining using antibodies specific for vascular smooth muscle cells and endothelial cells. The expression of pro-inflammatory and pro-remodeling genes was analyzed using quantitative RT-PCR. To detect the influx of inflammatory cells after treatment with silica, the lungs were stained using antibodies specific for CD107b and LY-6B.
Results: Mice 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, plexiform formation, 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.
Conclusions: These data suggest that silica promotes the damage of the pulmonary vasculature through mechanisms that might involve endothelial dysfunction, inflammation, and vascular remodeling.