title: Pulmonary hypertension and vascular remodeling in mice exposed to crystalline silica.
abstract: 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.
  
  
  
  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 lung histopathology.
  
  
  
  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, 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.
  
  
  
  We 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.
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville, Louisville, KY, 40202, USA. igor.zelko@louisville.edu.|Department of Biochemisry and Molecular Genetics, University of Louisville, Louisville, KY, 40202, USA. igor.zelko@louisville.edu.
authors.forename: Igor N
authors.initials: IN
authors.lastname: Zelko
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville, Louisville, KY, 40202, USA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Zhu
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville, Louisville, KY, 40202, USA.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Ritzenthaler
authors.affiliation: Department of Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, University of Louisville, Louisville, KY, 40202, USA.|Robley Rex VA Medical Center, Louisville, KY, 40202, USA.
authors.forename: Jesse
authors.initials: J
authors.lastname: Roman
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced* / Q000473:pathology*; D017380:Hypertrophy, Right Ventricular / Q000139:chemically induced / Q000473:pathology; D007249:Inflammation / Q000139:chemically induced / Q000473:pathology; D007278:Injections, Spinal; D008168:Lung / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000150:complications / Q000473:pathology; D012822:Silicon Dioxide / Q000633:toxicity*; D012829:Silicosis / Q000473:pathology*; D066253:Vascular Remodeling / Q000187:drug effects*
chemical_list: D016326:Extracellular Matrix Proteins; D012822:Silicon Dioxide; D003094:Collagen
keywords: Animal model; Pulmonary hypertension; Silicosis; Vascular remodeling