Role of SOD3 in silica-related lung fibrosis and pulmonary vascular remodeling

Igor N Zelko,Jesse Roman,Jianxin Zhu

doi:10.1186/s12931-018-0933-6

Abstract

BackgroundWork-place exposure to silica dust may lead to progressive lung inflammation culminating in the development of silicosis, an irreversible condition that can be complicated by onset of pulmonary hypertension (PH). The molecular mechanisms leading to the development of PH and lung fibrosis in response to silica are not well understood. Oxidant/antioxidant imbalance in the lung may promote fibroproliferation and vascular smooth muscle proliferation, ultimately leading to the development of PH. Herein, we analyze the development of PH and lung fibrosis in mice deficient in extracellular superoxide dismutase (SOD3), an enzyme with anti-oxidant activity.MethodsPH and silicosis were induced in wild-type and Sod3−/− mice through intratracheal injection of crystalline silica at dose 0.4 g/kg. Pulmonary hypertension and lung fibrosis were characterized by changes in right ventricular systolic pressure (RVSP) and collagen deposition 28 days following silica injections. Vascular remodeling was analyzed using immunohistochemistry and morphometric analysis. The expression of genes were analyzed using qRT-PCR and Western blot.ResultsC57BL6 mice exposed to silica showed attenuated expression of Sod3 in the lung suggesting a protective role for Sod3. Consistent with this, Sod3−/− mice developed more severe fibrotic inflammatory nodules with increased collagen deposition. Furthermore, the expression of genes involved in tissue remodeling (Timp1), fibrotic lesion formation (Fsp1) and inflammatory response (Mcp1) were significantly elevated in Sod3−/− mice compared to Sod3+/+ mice treated with silica. Infiltration of neutrophils and activated macrophages into affected lung was significantly higher in Sod3 deficient mice. In addition, silica produced more profound effects on elevation of RVSP in Sod3−/− compared to wild-type littermate. Increase in RVSP was concomitant with hypertrophy of pulmonary arteries located in silicotic nodules of both mouse strains, however, vascular remodeling in unaffected areas of lung was detected only in Sod3−/− mice.ConclusionsOur data suggest that Sod3 and extracellular oxidative stress may play an important role in the development of pneumoconiosis and pulmonary vascular remodeling following exposure to environmental and occupational silica.

Highlights

The occupational exposure to crystalline silica during coal mining, sand blasting, volcanic eruption and wind erosion remains a significant hazard worldwide
Since crystalline silica is a strong promoter of inflammatory responses in pulmonary cells, mostly through the induction of a burst of reactive oxygen species in affected areas of the lung, we decided to explore the role of an antioxidant enzyme in the development of lung fibrosis and pulmonary vascular remodeling leading to pulmonary hypertension in mice treated with silica [13]
Silica exposure is associated with reduction in SOD3 expression In order to explore the role of oxidative stress and superoxide dismutases in the development of pulmonary hypertension and silicosis, we began by analyzing the expression of three isoforms of superoxide dismutases in the lungs of control and silica-treated wild-type mice

Summary

Introduction

The occupational exposure to crystalline silica during coal mining, sand blasting, volcanic eruption and wind erosion remains a significant hazard worldwide. The pathogenesis of interstitial lung diseases and pulmonary hypertension is incompletely understood, recent literature points to the important role of an oxidant/antioxidant imbalance in the development of these serious disorders. Since crystalline silica is a strong promoter of inflammatory responses in pulmonary cells, mostly through the induction of a burst of reactive oxygen species in affected areas of the lung, we decided to explore the role of an antioxidant enzyme in the development of lung fibrosis and pulmonary vascular remodeling leading to pulmonary hypertension in mice treated with silica [13]. Work-place exposure to silica dust may lead to progressive lung inflammation culminating in the development of silicosis, an irreversible condition that can be complicated by onset of pulmonary hypertension (PH). We analyze the development of PH and lung fibrosis in mice deficient in extracellular superoxide dismutase (SOD3), an enzyme with anti-oxidant activity. The expression of genes were analyzed using qRT-PCR and Western blot

Methods

Results

Discussion

Conclusion