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

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.

• Authors: Yunlong Lei, Kui Wang, Xuefeng Li, Yi Li, Xuping Feng, Jing Zhou, Zhe Zhang, Canhua Huang, Tao Zhang
• Journal: Clinical science (London, England : 1979) (Clin Sci (Lond)) Vol. 133 Issue 7 Pg. 789-804 (04 15 2019) ISSN: 1470-8736 [Electronic] England
• PMID: 30902828 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 The Author(s).

Chemical References

• ANXA2 protein, human
• Annexin A2
• Anxa2 protein, mouse
• Interleukin-6
• NF-kappa B
• Scorpion Venoms
• interleukin-6, mouse
• Chlorotoxin
• Bleomycin

Topics

• A549 Cells
• Animals
• Annexin A2 (antagonists & inhibitors, genetics, metabolism)
• Bleomycin
• Disease Models, Animal
• Exosomes (metabolism)
• Humans
• Interleukin-6 (metabolism)
• Lung (drug effects, metabolism, pathology)
• Mice, Inbred C57BL
• Mice, Knockout
• NF-kappa B (metabolism)
• Pneumonia (chemically induced, metabolism, pathology, prevention & control)
• Protein Transport
• Pulmonary Fibrosis (chemically induced, metabolism, pathology, prevention & control)
• Scorpion Venoms (pharmacology)