Cell-surface translocation of annexin A2 contributes to bleomycin-induced pulmonary fibrosis by mediating inflammatory response in mice.

Yunlong Lei,Yi Li,Jing Zhou,Zhe Zhang,Xuefeng Li,Canhua Huang,Tao Zhang,Xuping Feng,Kui Wang

doi:10.1042/cs20180687

Abstract

Bleomycin, a widely used anti-cancer drug, may give rise to pulmonary fibrosis, a serious side effect which is associated with significant morbidity and mortality. Despite the intensive efforts, the precise pathogenic mechanisms of pulmonary fibrosis still remain to be clarified. Our previous study showed that bleomycin bound directly to annexin A2 (ANXA2, or p36), leading to development of pulmonary fibrosis by impeding transcription factor EB (TFEB)-induced autophagic flux. Here, we demonstrated that ANXA2 also played a critical role in bleomycin-induced inflammation, which represents another major cause of bleomycin-induced pulmonary fibrosis. We found that bleomycin could induce the cell surface translocation of ANXA2 in lung epithelial cells through exosomal secretion, associated with enhanced interaction between ANXA2 and p11. Knockdown of ANXA2 or blocking membrane ANXA2 mitigated bleomycin-induced activation of nuclear factor (NF)-κB pathway and production of pro-inflammatory cytokine IL-6 in lung epithelial cells. ANXA2-deficient (ANXA2-/-) mice treated with bleomycin exhibit reduced pulmonary fibrosis along with decreased cytokine production compared with bleomycin-challenged wild-type mice. Further, the surface ANXA2 inhibitor TM601 could ameliorate fibrotic and inflammatory response in bleomycin-treated mice. Taken together, our results indicated that, in addition to disturbing autophagic flux, ANXA2 can contribute to bleomycin-induced pulmonary fibrosis by mediating inflammatory response.

Highlights

Bleomycin, a member of the glycopeptides group of antibiotics, is used for the treatment of testicular carcinoma, lymphoma, and squamous cell carcinoma [1]
We found that ANXA2-bleomycin binding inhibited transcription factor EB (TFEB)-induced autophagy flux, which contributed to bleomycin-induced pulmonary fibrosis [30]
Several recent studies found that ANXA2 could induce the activation of nuclear factor-κB (NF-κB) pathway which has been demonstrated as an important cue of inflammation and pulmonary fibrosis [5,36,37,38,39]

Summary

Introduction

A member of the glycopeptides group of antibiotics, is used for the treatment of testicular carcinoma, lymphoma, and squamous cell carcinoma [1]. Continuous and high-dose medication of bleomycin causes severe pulmonary fibrosis, the most common and clinically significant adverse effect [1]. Intratracheal administration of bleomycin has been widely used as an experimental model of lung fibrosis which resembles human pulmonary fibrosis biochemically and histologically [2,3,4,5]. Much of our understanding of the mechanisms underlying human idiopathic pulmonary fibrosis (IPF) has focused on the studies of bleomycin-induced pulmonary fibrosis in mouse models [5]. There is a lack of detailed, precise molecular mechanisms of bleomycin-induced pulmonary fibrosis, its molecular targets. Identifying the direct target of bleomycin will shed light on better understanding of the pathologic mechanisms of pulmonary fibrosis

Methods

Results

Conclusion