Raltegravir Attenuates Experimental Pulmonary Fibrosis In Vitro and In Vivo.

Xue Zhang,Defang Li,Hongbo Wang,Haidi Huang,Wanglin Jiang,Guanghua Zhang

doi:10.3389/fphar.2019.00903

Abstract

Raltegravir, an inhibitor of human immunodeficiency virus-1 (HIV-1) integrase, has been used to treat HIV/acquired immunodeficiency syndrome; however, its therapeutic effects on pulmonary fibrosis have not been investigated. In this study, the in vitro effects of raltegravir (RAV) on transforming growth factor beta 1 (TGF-β1)-induced pulmonary fibrosis on L929 mouse fibroblasts were investigated. In addition, the effects of RAV on an in vivo pulmonary fibrosis model induced by intratracheal instillation of bleomycin were investigated. The proliferation of L929 cells was inhibited after RAV treatment. Meanwhile, the in vitro and in vivo protein expression of nucleotide-binding oligomerization domain-like receptor 3 (NLRP3), high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), prolyl hydroxylase domain protein 2, phosphorylated nuclear factor-κB (p-NF-κB), hypoxia-inducible factor-1α (HIF-1α), collagens I and III was reduced relative to TGF-β1 or the bleomycin group. Raltegravir ameliorated pulmonary fibrosis by reducing the pathology score, collagen deposition, and expression of α-smooth muscle actin, NLRP3, HMGB1, TLR4, inhibitor of kappa B, p-NF-κB, HIF-1α, collagen I, and collagen III. The results of this study demonstrate that RAV attenuated experimental attenuates pulmonary fibrosis by inhibiting NLRP3 activation.

Highlights

Idiopathic pulmonary fibrosis (IPF) is an irreversible, chronic, progressive, and life-threatening disease with limited treatments and poor prognosis
Rabbit polyclonal antibodies against nucleotide-binding oligomerization domain-like receptor 3 (NLRP3), high-mobility group box 1 (HMGB1), toll-like receptor 4 (TLR4), phosphorylated nuclear factor-κB (p-NF-κB), prolyl hydroxylase domain protein 2 (PHD2), alpha smooth muscle actin (α-SMA), collagens I and III, and mouse polyclonal antibodies against inhibitor of kappa B (IκBα) and hypoxiainducible factor-1α (HIF-1α) were purchased from Abcam Biotechnology (Shanghai, China)
The results showed that BAY11-7082 alone reduced p-NF-κB and HMGB1 expression and inhibited cell proliferation, but did not reduce NLRP3 and TLR4 expression (Figures 8A1, A2)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is an irreversible, chronic, progressive, and life-threatening disease with limited treatments and poor prognosis. The disease accelerates during acute IPF exacerbation (Hyzy et al, 2007; Lopez et al, 2009; Richeldi et al, 2011; Margaritopoulos et al, 2012). The pathogenesis of IPF is not completely understood, and current therapies are limited to those that reduce the rate of functional decline in patients with mild to moderate disease (Mora et al, 2017). More severe hypoxia occurs, leading to the exacerbation of IPF. HIF-1α overexpression results in the proliferation and transformation of fibroblasts

Methods

Results

Conclusion