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Mitochondrial antiviral signalling protein is crucial for the development of pulmonary fibrosis


Abstract

Danger signals, or damage-associated molecular patterns (DAMPs), instigate mitochondrial innate immune responses wherein Mitochondrial Antiviral Signalling 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 been identified yet. A possibility whether the MAVS signalling can be modulated by currently existing drugs has not been explored, either. Here, using an established model of pulmonary fibrosis, we demonstrate that MAVS plays as a critical mediator of multiple DAMPs signalling pathways and the consequent lung fibrosis after bleomycin-induced injury in vivo. After bleomycin injury, the expression of MAVS was mainly observed in macrophages. In addition, multimeric MAVS aggregation, a key event of MAVS signalling activation, was significantly increased and persisted in bleomycin-injured lungs. Interestingly, 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 Pirfenidone or Nintedanib, two approved drugs for IPF treatment, were not related to the modulation of MAVS or its signalling. Importantly, multimeric MAVS aggregation was significantly increased in lungs from the patients with IPF as well. In conclusion, MAVS may play an important role in the development of pulmonary fibrosis, and targeting MAVS with BH3 mimetics may provide a novel therapeutic strategy for IPF, a major unmet disorder.

Footnotes

This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.

Conflict of interest: Dr. Yan reports grants from National Institutes of Health, during the conduct of the study;.

Conflict of interest: Dr. Kim has nothing to disclose.

Conflict of interest: Dr. Lee has nothing to disclose.

Conflict of interest: Dr. Yoon has nothing to disclose.

Conflict of interest: Dr. SHIN has nothing to disclose.

Conflict of interest: Dr. Lee has nothing to disclose.

Conflict of interest: Dr. Rosas has nothing to disclose.

Conflict of interest: Dr. Herzog reports personal fees from Boehringer, personal fees from MErck, personal fees from Genentech, grants from Boehringer, grants from Sanofi, grants from Bristol Myers, outside the submitted work;.

Conflict of interest: Dr. Cruz has nothing to disclose.

Conflict of interest: Dr. Kaminski reports personal fees from Biogen Idec, Boehringer Ingelheim, Third Rock, Miragen, Pliant, personal fees from Samumed, NuMedii, Indaloo, Theravance, LifeMax, Three Lake Partners, outside the submitted work; In addition, Dr. Kaminski has a patent New Threapies in Pulmonary Fibrosis with royalties paid to Biotech, and a patent Peripheral Blood Gene Expression issued and Serves as Deputy Editor of Thorax, BMJ. .Dr. Kaminski reports personal fees from Biogen Idec, personal fees from Boehringer Ingelheim, personal fees from Third Rock, personal fees from MMI, non-financial support from Miragen, personal fees from Pliant, personal fees from Samumed, personal fees from NuMedii, personal fees from Indaloo, outside the submitted work; In addition, Dr. Kaminski has a patent New Threapies in Pulmonary Fibrosis with royalties paid to Biotech, and a patent Peripheral Blood Gene Expression issued and Serves as Deputy Editor of Thorax, BMJ.

Conflict of interest: Dr. Kang has nothing to disclose.

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

sumber : https://erj.ersjournals.com/content/early/2020/10/15/13993003.00652-2020?utm_source=TrendMD&utm_medium=cpc&utm_campaign=European_Respiratory_Journal_TrendMD_0

 
 

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