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Mitochondrial antiviral signaling protein is crucial for the development of pulmonary fibrosis
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Selasa, 27 Apr 2021 10:18:56

Sang-Hun Kim, Jung Yeon Lee, Chang Min Yoon, Hyeon Jun Shin, Sei Won Lee, Ivan Rosas, Erica Herzog, Charles S. Dela Cruz, Naftali Kaminski, Min-Jong Kang

European Respiratory Journal 2021 57: 2000652; DOI: 10.1183/13993003.00652-2020

Abstract

Danger signals, or damage-associated molecular patterns (DAMPs), instigate mitochondrial innate immune responses wherein mitochondrial antiviral signaling protein (MAVS) functions as a key platform molecule to mediate them. The role of MAVS in the pathogenesis of idiopathic pulmonary fibrosis (IPF), however, has not yet been identified. Whether MAVS signalling can be modulated by currently existing drugs has also not been explored.

We used an established model of pulmonary fibrosis to demonstrate that MAVS is a critical mediator of multiple DAMP signalling pathways and the consequent lung fibrosis after bleomycin-induced injury in vivo.

After bleomycin injury, MAVS expression was mainly observed in macrophages. Multimeric MAVS aggregation, a key event of MAVS signalling activation, was significantly increased and persisted in bleomycin-injured lungs. A proapoptotic BH3 mimetic, ABT-263, attenuated the expression of MAVS and its signalling and, consequently, the development of experimental pulmonary fibrosis. In contrast, the therapeutic effects of nintedanib and pirfenidone, two drugs approved for IPF treatment, were not related to the modulation of MAVS or its signalling. Multimeric MAVS aggregation was significantly increased in lungs from IPF patients as well.

MAVS may play an important role in the development of pulmonary fibrosis, and targeting MAVS with BH3 mimetics may provide a novel and much needed therapeutic strategy for IPF.

MAVS may play a critical role in the development of pulmonary fibrosis, and targeting MAVS or its signalling by proapoptotic BH3 mimetics may be a feasible strategy for the treatment of IPF. https://bit.ly/31rIsmZ

Footnotes

  • This article has an editorial commentary: https://doi.org/10.1183/13993003.04500-2020

  • This article has supplementary material available from erj.ersjournals.com

  • Author contributions: Conceived the idea and designed the experiments (S-H. Kim, J.Y. Lee, M-J. Kang); performed experiments (S-H. Kim, J.Y. Lee, H.J. Shin, C.M. Yoon, S.W. Lee); provided important reagents/tools (S.W. Lee, C.M. Yoon, I. Rosas, N. Kaminski); provided scientific insight (S-H. Kim, E. Herzog, C. Dela Cruz, N. Kaminski, M-J. Kang); analysed data (S-H. Kim, E. Herzog, M-J. Kang); drafted the manuscript (S-H. Kim, J.Y. Lee, M-J. Kang); all of the authors reviewed the manuscript.

  • Conflict of interest: S-H. Kim has nothing to disclose.

  • Conflict of interest: J.Y. Lee has nothing to disclose.

  • Conflict of interest: C.M. Yoon has nothing to disclose.

  • Conflict of interest: H.J. Shin has nothing to disclose.

  • Conflict of interest: S.W. Lee has nothing to disclose.

  • Conflict of interest: I. Rosas has nothing to disclose.

  • Conflict of interest: E. Herzog reports personal fees from Boehringer Ingelheim, Merck and Genentech, and grants from Boehringer Ingelheim, Sanofi and Bristol Myers, outside the submitted work.

  • Conflict of interest: C. Dela Cruz has nothing to disclose.

  • Conflict of interest: N. Kaminski reports personal fees from Biogen Idec (consultant), Boehringer Ingelheim (consultant), Third Rock (consultant), Pliant (Advisory Board), Samumed (consultant), NuMedii (consultant), Indaloo (consultant), Theravance (consultant), LifeMax (consultant) and Three Lake Partners (Scientific Advisory Committee), and non-financial support from Miragen (for pulmonary fibrosis work), outside the submitted work; and has a patent New Threapies in Pulmonary Fibrosis with royalties paid to Biotech, a patent Peripheral Blood Gene Expression issued, and serves as Deputy Editor of Thorax, BMJ.

  • Conflict of interest: M-J. Kang has nothing to disclose.

  • Support statement: These studies were supported by National Institute on Aging (grant: R01AG053495 to M-J. Kang) and the National Heart, Lung, and Blood Institute (grant: R01HL130283 to M-J. Kang). Funding information for this article has been deposited with the Crossref Funder Registry.

  • Received March 16, 2020.
  • Accepted October 12, 2020.