Effect of SIS3 on Extracellular Matrix Remodeling and Repair in a Lipopolysaccharide-Induced ARDS Rat Model.

Qiong Liang,Liao Pinhu,Yueyong Li,Xia Huang,Weigui Luo,Yujie Jiang,Jin Nong,Xiang Chen,Qiqing Lin,Suren Rao Sooranna,Chunyan Qin,Jian Song

doi:10.1155/2020/6644687

Abstract

The remodeling of the extracellular matrix (ECM) in the parenchyma plays an important role in the development of acute respiratory distress syndrome (ARDS), a disease characterized by lung injury. Although it is clear that TGF-β1 can modulate the expression of the extracellular matrix (ECM) through intracellular signaling molecules such as Smad3, its role as a therapeutic target against ARDS remains unknown. In this study, a rat model was established to mimic ARDS via intratracheal instillation of lipopolysaccharide (LPS). A selective inhibitor of Smad3 (SIS3) was intraperitoneally injected into the disease model, while phosphate-buffered saline (PBS) was used in the control group. Animal tissues were then evaluated using histological analysis, immunohistochemistry, RT-qPCR, ELISA, and western blotting. LPS was found to stimulate the expression of RAGE, TGF-β1, MMP2, and MMP9 in the rat model. Moreover, treatment with SIS3 was observed to reverse the expression of these molecules. In addition, pretreatment with SIS3 was shown to partially inhibit the phosphorylation of Smad3 and alleviate symptoms including lung injury and pulmonary edema. These findings indicate that SIS3, or the blocking of TGF-β/Smad3 pathways, could influence remodeling of the ECM and this may serve as a therapeutic strategy against ARDS.

Highlights

Acute respiratory distress syndrome (ARDS) is a diffuse pulmonary parenchymal injury characterized by injury of the pulmonary epithelium and vascular endothelial cells as well as inflammatory infiltration, hyaline membrane formation, matrix repair, and pulmonary interstitial fibrosis
LPS-Induced Receptor for advanced glycation end-products (RAGE), transforming growth factor- (TGF-)β1, MMP2, and MMP9 Genes Were Suppressed by selective inhibitor of small mothers against decapentaplegic 3 (Smad3) (SIS3) in the ARDS Rat Model
RAGE, TGF-β1, MMP2, and MMP9 mRNA expression was found to be increased in lung homogenates after LPS induction

Summary

Introduction

Acute respiratory distress syndrome (ARDS) is a diffuse pulmonary parenchymal injury characterized by injury of the pulmonary epithelium and vascular endothelial cells as well as inflammatory infiltration, hyaline membrane formation, matrix repair, and pulmonary interstitial fibrosis. Lipopolysaccharide (LPS) is a major component of the cell walls of gram-negative bacteria that possesses powerful inflammatory effects and plays a significant role in the occurrence and progression of ARDS [1]. Extracellular matrix (ECM) metabolism serves in the regulation of lung function and morphology. ECM remodeling encompasses changes in fibrin collagen, the basement membrane, and elastin. Matrix cells synthesize and secrete extracellular polysaccharides and macromolecules, such as proteins and proteoglycans, which are distributed on the cell surface or between cells, forming a network structure between cells.

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