Cargando…
Lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage M2 metabolic program
INTRODUCTION: Pulmonary fibrosis (PF) is a fatal disease with a variable and unpredictable course. Effective clinical treatment for PF remains a challenge due to low drug accumulation in lungs and imbalanced polarization of pro/anti-fibrotic macrophages. OBJECTIVES: To identify the alteration of imm...
Autores principales: | , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936526/ https://www.ncbi.nlm.nih.gov/pubmed/36725191 http://dx.doi.org/10.1016/j.jare.2022.04.012 |
_version_ | 1784890251042357248 |
---|---|
author | Wang, Huirui Gao, Yinghui Wang, Li Yu, Yang Zhang, Jiaozhen Liu, Chunyu Song, Yaxin Xu, Haochuan Wang, Jingcheng Lou, Hongxiang Dong, Ting |
author_facet | Wang, Huirui Gao, Yinghui Wang, Li Yu, Yang Zhang, Jiaozhen Liu, Chunyu Song, Yaxin Xu, Haochuan Wang, Jingcheng Lou, Hongxiang Dong, Ting |
author_sort | Wang, Huirui |
collection | PubMed |
description | INTRODUCTION: Pulmonary fibrosis (PF) is a fatal disease with a variable and unpredictable course. Effective clinical treatment for PF remains a challenge due to low drug accumulation in lungs and imbalanced polarization of pro/anti-fibrotic macrophages. OBJECTIVES: To identify the alteration of immunometabolism in the pulmonary macrophages and investigate the feasibility of specific inhibition of M2 activation of macrophages as an effective anti-PF strategy in vivo. METHODS: The high-content screening system was used to select lung-specific homing compounds that can modulate macrophage polarization. Imaging mass spectrometry (IMS) conjugated with chemical proteomics approach was conducted to explore the cells and proteins targeted by diphenyleneiodonium chloride (DPI). A bleomycin-induced fibrotic mouse model was established to examine the in vivo effect of DPI. RESULTS: Pulmonary macrophages of PF at late stage exhibited predominantly the M2 phenotype with decreased glycolysis metabolism. DPI was demonstrated to inhibit profibrotic activation of macrophages in the preliminary screening. Notably, IMS conjugated with chemical proteomics approach revealed DPI specifically targeted pulmonary macrophages, leading to the efficient protection from bleomycin-induced pulmonary fibrosis in mice. Mechanistically, DPI upregulated glycolysis and suppressed M2 programming in fibrosis mice, thus resulting in pro-fibrotic cytokine inhibition, hydroxyproline biosynthesis, and collagen deposition, with a concomitant increase in alveolar airspaces. CONCLUSIONS: DPI mediated glycolysis in lung and accordingly suppressed M2 programming, resulting in improved lung fibrosis. |
format | Online Article Text |
id | pubmed-9936526 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-99365262023-02-18 Lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage M2 metabolic program Wang, Huirui Gao, Yinghui Wang, Li Yu, Yang Zhang, Jiaozhen Liu, Chunyu Song, Yaxin Xu, Haochuan Wang, Jingcheng Lou, Hongxiang Dong, Ting J Adv Res Original Article INTRODUCTION: Pulmonary fibrosis (PF) is a fatal disease with a variable and unpredictable course. Effective clinical treatment for PF remains a challenge due to low drug accumulation in lungs and imbalanced polarization of pro/anti-fibrotic macrophages. OBJECTIVES: To identify the alteration of immunometabolism in the pulmonary macrophages and investigate the feasibility of specific inhibition of M2 activation of macrophages as an effective anti-PF strategy in vivo. METHODS: The high-content screening system was used to select lung-specific homing compounds that can modulate macrophage polarization. Imaging mass spectrometry (IMS) conjugated with chemical proteomics approach was conducted to explore the cells and proteins targeted by diphenyleneiodonium chloride (DPI). A bleomycin-induced fibrotic mouse model was established to examine the in vivo effect of DPI. RESULTS: Pulmonary macrophages of PF at late stage exhibited predominantly the M2 phenotype with decreased glycolysis metabolism. DPI was demonstrated to inhibit profibrotic activation of macrophages in the preliminary screening. Notably, IMS conjugated with chemical proteomics approach revealed DPI specifically targeted pulmonary macrophages, leading to the efficient protection from bleomycin-induced pulmonary fibrosis in mice. Mechanistically, DPI upregulated glycolysis and suppressed M2 programming in fibrosis mice, thus resulting in pro-fibrotic cytokine inhibition, hydroxyproline biosynthesis, and collagen deposition, with a concomitant increase in alveolar airspaces. CONCLUSIONS: DPI mediated glycolysis in lung and accordingly suppressed M2 programming, resulting in improved lung fibrosis. Elsevier 2022-04-29 /pmc/articles/PMC9936526/ /pubmed/36725191 http://dx.doi.org/10.1016/j.jare.2022.04.012 Text en © 2022 The Authors. Published by Elsevier B.V. on behalf of Cairo University. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Original Article Wang, Huirui Gao, Yinghui Wang, Li Yu, Yang Zhang, Jiaozhen Liu, Chunyu Song, Yaxin Xu, Haochuan Wang, Jingcheng Lou, Hongxiang Dong, Ting Lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage M2 metabolic program |
title | Lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage M2 metabolic program |
title_full | Lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage M2 metabolic program |
title_fullStr | Lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage M2 metabolic program |
title_full_unstemmed | Lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage M2 metabolic program |
title_short | Lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage M2 metabolic program |
title_sort | lung specific homing of diphenyleneiodonium chloride improves pulmonary fibrosis by inhibiting macrophage m2 metabolic program |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9936526/ https://www.ncbi.nlm.nih.gov/pubmed/36725191 http://dx.doi.org/10.1016/j.jare.2022.04.012 |
work_keys_str_mv | AT wanghuirui lungspecifichomingofdiphenyleneiodoniumchlorideimprovespulmonaryfibrosisbyinhibitingmacrophagem2metabolicprogram AT gaoyinghui lungspecifichomingofdiphenyleneiodoniumchlorideimprovespulmonaryfibrosisbyinhibitingmacrophagem2metabolicprogram AT wangli lungspecifichomingofdiphenyleneiodoniumchlorideimprovespulmonaryfibrosisbyinhibitingmacrophagem2metabolicprogram AT yuyang lungspecifichomingofdiphenyleneiodoniumchlorideimprovespulmonaryfibrosisbyinhibitingmacrophagem2metabolicprogram AT zhangjiaozhen lungspecifichomingofdiphenyleneiodoniumchlorideimprovespulmonaryfibrosisbyinhibitingmacrophagem2metabolicprogram AT liuchunyu lungspecifichomingofdiphenyleneiodoniumchlorideimprovespulmonaryfibrosisbyinhibitingmacrophagem2metabolicprogram AT songyaxin lungspecifichomingofdiphenyleneiodoniumchlorideimprovespulmonaryfibrosisbyinhibitingmacrophagem2metabolicprogram AT xuhaochuan lungspecifichomingofdiphenyleneiodoniumchlorideimprovespulmonaryfibrosisbyinhibitingmacrophagem2metabolicprogram AT wangjingcheng lungspecifichomingofdiphenyleneiodoniumchlorideimprovespulmonaryfibrosisbyinhibitingmacrophagem2metabolicprogram AT louhongxiang lungspecifichomingofdiphenyleneiodoniumchlorideimprovespulmonaryfibrosisbyinhibitingmacrophagem2metabolicprogram AT dongting lungspecifichomingofdiphenyleneiodoniumchlorideimprovespulmonaryfibrosisbyinhibitingmacrophagem2metabolicprogram |