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Respiratory Research

, 17:160

First Online: 28 November 2016Received: 08 September 2016Accepted: 22 November 2016


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.

KeywordsSilicosis Pulmonary hypertension Vascular remodeling Animal model AbbreviationsCOPDChronic obstructive pulmonary disease

CTGFConnective tissue growth factor

IL-6Interleukin 6

LY-6BLymphocyte antigen 6 complex, locus B

MCP-1Monocyte chemoattractant protein – 1

MMP-2Matric metallopeptidase – 2

PAHPulmonary arterial hypertension

PECAM-1Platelet and endothelial cell adhesion molecule – 1

PF4Platelet factor 4

RVRight ventricle

RVSPRight ventricular systolic pressure

TIMP-1Tissue inhibitor of metalloproteinase – 1

TNF-αTumor necrosis factor alpha

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Autor: Igor N. Zelko - Jianxin Zhu - Jeffrey D. Ritzenthaler - Jesse Roman

Fuente: https://link.springer.com/article/10.1186/s12931-016-0478-5

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