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

Abstract:

BACKGROUND: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). 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. METHODS:PH 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. RESULTS:C57BL6 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. CONCLUSIONS:Our 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.

journal_name

Respir Res

journal_title

Respiratory research

authors

Zelko IN,Zhu J,Roman J

doi

10.1186/s12931-018-0933-6

subject

Has Abstract

pub_date

2018-11-20 00:00:00

pages

221

issue

1

eissn

1465-9921

issn

1465-993X

pii

10.1186/s12931-018-0933-6

journal_volume

19

pub_type

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