Anti-Fibrotic Effects of Low Toxic Microcystin-RR on Bleomycin-Induced Pulmonary Fibrosis: A Comparison with Microcystin-LR.

Jie Wang,Jiaqi Kang,Yaping Wang,Xiufen Zheng,Lizhi Xu,Yan Ren,Zhenqian Huang

doi:10.3389/fphar.2021.675907

Abstract

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pulmonary disease characterized with radiographically evident pulmonary infiltrates and extracellular matrix deposition with limited treatment options. We previously described that microcystin-LR (MC-LR) reduces transforming growth factor (TGF)-β1/Smad signaling and ameliorates pulmonary fibrosis in bleomycin (BLM)-induced rat models. In the present study, we further demonstrate that microcystin-RR (MC-RR), an MC congener with lower toxicity than MC-LR, exerted an anti-fibrotic effect on BLM-induced pulmonary fibrosis rodent models and compared it with MC-LR. Our data show that MC-RR treatment attenuated BLM-associated pulmonary inflammation and collagen deposition in both therapeutic and preventive models. MC-RR reduced the expression of fibrotic markers, including vimentin, α-smooth muscle actin, collagen 1α1, and fibronectin, in rat pulmonary tissues. Furthermore, the core features of BLM-induced pulmonary fibrotic lesions were better alleviated by MC-RR than by MC-LR. MC-RR treatment substantially decreased the number of pulmonary M2 macrophages. In vitro, MC-RR attenuated the epithelial-mesenchymal transition and fibroblast-myofibroblast transition triggered by M2 macrophages. Therefore, we highlight MC-RR as a promising molecule for developing therapeutic and prophylactic strategies against IPF, a refractory lung disease.

Highlights

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease characterized with inflammation, fibroblast accumulation, and collagen deposition (Lederer and Martinez, 2018; Sgalla et al, 2018; Chanda et al, 2019)
We have previously described that MC-LR exhibits therapeutic potential for pulmonary fibrosis (Wang et al, 2020) by demonstrating its ability to attenuate the macrophage polarization toward the CD206+ M2-like phenotype
Consistent with histology results, MC-RR notably reduced the content of HYP, a representative marker for collagen deposition, in the lung tissue that was highly elevated in BLM model rats (Figure 1E)

Summary

Introduction

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease characterized with inflammation, fibroblast accumulation, and collagen deposition (Lederer and Martinez, 2018; Sgalla et al, 2018; Chanda et al, 2019). Excessive fibrosis destroys the lung architecture, leading to respiratory dysfunction and failure. Anti-Fibrotic Effects of Microcystin-RR (FDA) approval for the treatment of IPF and are mainly used to decelerate the rate of decline in forced vital capacity (Martinez and Lederer, 2018; Collins and Raghu, 2019; Somogyi et al, 2019). Two distinct populations of macrophages are widely described in pulmonary fibrosis pathogenesis, namely, classically activated (M1) macrophages and alternatively activated (M2) macrophages. Strategies aimed at modulating lung macrophages are considered promising for the prevention and treatment of IPF (Morse et al, 2019; Ucero et al, 2019; Pan et al, 2021)

Methods

Results

Conclusion