Contribution of Thrombospondin-1 and -2 to Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome.

Qiang Li,Shu Han,Jiang Yuan,Xiaoxiao Fu,Sandra Helena Penha Oliveira

doi:10.1155/2021/8876484

Abstract

Thrombospondin (TSP) proteins have been shown to impact T-cell adhesion, migration, differentiation, and apoptosis. Thrombospondin-1 (TSP-1) is specifically upregulated in several inflammatory diseases and can effectively promote lipopolysaccharide- (LPS-) induced inflammation. In contrast, thrombospondin-2 (TSP-2) has been associated with activation of “anti-inflammatory” T-regulatory cells (Tregs). In this study, we investigated the effects of both TSP-1 and TSP-2 overexpression on macrophage polarization and activation in vitro and in vivo. We analyzed the effects of TSP-1 and TSP-2 on inflammation, vascular endothelial permeability, edema, ultrastructural morphology, and apoptosis in lung tissues of an ARDS mouse model and cultured macrophages. Our results demonstrated that TSP-2 overexpression effectively attenuated LPS-induced ARDS in vivo and promoted M2 macrophage phenotype polarization in vitro. Furthermore, TSP-2 played a role in regulating pulmonary vascular barrier leakage by activating the PI3K/Akt pathway. Overall, our findings indicate that TSP-2 can modulate inflammation and could therefore be a potential therapeutic target against LPS-induced ARDS.

Highlights

Acute respiratory distress syndrome (ARDS) is a diffuse alveolar injury caused by lung infection or systemic inflammation/sepsis in multiple patients
We investigated the role of TSP-1 and TSP2 on in vitro macrophage polarization and their potential to regulate the phosphatidyl inositol-3 kinase (PI3K)/Akt signaling pathway
LPS treatment of TSP-1-overexpressing MH-S cells did not alter CD38 and Fpr-2 expression (Figures 1(c) and 1(h)), but TSP-2 overexpression reduced CD38 and Fpr-2 expression compared to vehicle control (Figures 1(d) and 1(i))

Summary

Introduction

Acute respiratory distress syndrome (ARDS) is a diffuse alveolar injury caused by lung infection or systemic inflammation/sepsis in multiple patients. Lung inflammation can disrupt alveolar endothelial and epithelial barriers and in turn enhance the influx of multiple cell types, including neutrophils, macrophages, and other inflammatory cells that subsequently release various inflammatory and cytotoxic mediators [1]. M1polarized macrophages are typically generated in response to microbial products or interferon- (IFN-) γ, and can efficiently produce proinflammatory cytokines, including interleukin(IL-) 6, IL-12, and tumor necrosis factor- (TNF-) α. These cytokines induce a polarized type I immune response that inhibits cell proliferation and induces tissue damage. M2polarized macrophages induce anti-inflammatory cytokines and promote tissue remodeling and wound healing [4]

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Conclusion