Cargando…

Two-Pore-Domain Potassium Channel TREK–1 Mediates Pulmonary Fibrosis through Macrophage M2 Polarization and by Direct Promotion of Fibroblast Differentiation

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and abnormal accumulation of extracellular matrix in the lungs. After lung injury, M2 macrophages mediate the pathogenesis of pulmonary fibrosis by secreting fibrotic cytokines that promote myof...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Yunna, Fu, Jiafeng, Han, Yang, Feng, Dandan, Yue, Shaojie, Zhou, Yan, Luo, Ziqiang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215911/
https://www.ncbi.nlm.nih.gov/pubmed/37238950
http://dx.doi.org/10.3390/biomedicines11051279
_version_ 1785048175549087744
author Zhang, Yunna
Fu, Jiafeng
Han, Yang
Feng, Dandan
Yue, Shaojie
Zhou, Yan
Luo, Ziqiang
author_facet Zhang, Yunna
Fu, Jiafeng
Han, Yang
Feng, Dandan
Yue, Shaojie
Zhou, Yan
Luo, Ziqiang
author_sort Zhang, Yunna
collection PubMed
description Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and abnormal accumulation of extracellular matrix in the lungs. After lung injury, M2 macrophages mediate the pathogenesis of pulmonary fibrosis by secreting fibrotic cytokines that promote myofibroblast activation. The TWIK-related potassium channel (TREK–1, also known as KCNK2) is a K2P channel that is highly expressed in cardiac, lung, and other tissues; it worsens various tumors, such as ovarian cancer and prostate cancer, and mediates cardiac fibrosis. However, the role of TREK–1 in lung fibrosis remains unclear. This study aimed to examine the effects of TREK–1 on bleomycin (BLM)-induced lung fibrosis. The results show that TREK–1 knockdown, mediated by the adenovirus or pharmacological inhibition of TREK–1 with fluoxetine, resulted in diminished BLM-induced lung fibrosis. TREK–1 overexpression in macrophages remarkably increased the M2 phenotype, resulting in fibroblast activation. Furthermore, TREK–1 knockdown and fluoxetine administration directly reduced the differentiation of fibroblasts to myofibroblasts by inhibiting the focal adhesion kinase (FAK)/p38 mitogen-activated protein kinases (p38)/Yes-associated protein (YAP) signaling pathway. In conclusion, TREK–1 plays a central role in the pathogenesis of BLM-induced lung fibrosis, which serves as a theoretical basis for the inhibition of TREK–1 as a potential therapy protocol for lung fibrosis.
format Online
Article
Text
id pubmed-10215911
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-102159112023-05-27 Two-Pore-Domain Potassium Channel TREK–1 Mediates Pulmonary Fibrosis through Macrophage M2 Polarization and by Direct Promotion of Fibroblast Differentiation Zhang, Yunna Fu, Jiafeng Han, Yang Feng, Dandan Yue, Shaojie Zhou, Yan Luo, Ziqiang Biomedicines Article Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and abnormal accumulation of extracellular matrix in the lungs. After lung injury, M2 macrophages mediate the pathogenesis of pulmonary fibrosis by secreting fibrotic cytokines that promote myofibroblast activation. The TWIK-related potassium channel (TREK–1, also known as KCNK2) is a K2P channel that is highly expressed in cardiac, lung, and other tissues; it worsens various tumors, such as ovarian cancer and prostate cancer, and mediates cardiac fibrosis. However, the role of TREK–1 in lung fibrosis remains unclear. This study aimed to examine the effects of TREK–1 on bleomycin (BLM)-induced lung fibrosis. The results show that TREK–1 knockdown, mediated by the adenovirus or pharmacological inhibition of TREK–1 with fluoxetine, resulted in diminished BLM-induced lung fibrosis. TREK–1 overexpression in macrophages remarkably increased the M2 phenotype, resulting in fibroblast activation. Furthermore, TREK–1 knockdown and fluoxetine administration directly reduced the differentiation of fibroblasts to myofibroblasts by inhibiting the focal adhesion kinase (FAK)/p38 mitogen-activated protein kinases (p38)/Yes-associated protein (YAP) signaling pathway. In conclusion, TREK–1 plays a central role in the pathogenesis of BLM-induced lung fibrosis, which serves as a theoretical basis for the inhibition of TREK–1 as a potential therapy protocol for lung fibrosis. MDPI 2023-04-26 /pmc/articles/PMC10215911/ /pubmed/37238950 http://dx.doi.org/10.3390/biomedicines11051279 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Yunna
Fu, Jiafeng
Han, Yang
Feng, Dandan
Yue, Shaojie
Zhou, Yan
Luo, Ziqiang
Two-Pore-Domain Potassium Channel TREK–1 Mediates Pulmonary Fibrosis through Macrophage M2 Polarization and by Direct Promotion of Fibroblast Differentiation
title Two-Pore-Domain Potassium Channel TREK–1 Mediates Pulmonary Fibrosis through Macrophage M2 Polarization and by Direct Promotion of Fibroblast Differentiation
title_full Two-Pore-Domain Potassium Channel TREK–1 Mediates Pulmonary Fibrosis through Macrophage M2 Polarization and by Direct Promotion of Fibroblast Differentiation
title_fullStr Two-Pore-Domain Potassium Channel TREK–1 Mediates Pulmonary Fibrosis through Macrophage M2 Polarization and by Direct Promotion of Fibroblast Differentiation
title_full_unstemmed Two-Pore-Domain Potassium Channel TREK–1 Mediates Pulmonary Fibrosis through Macrophage M2 Polarization and by Direct Promotion of Fibroblast Differentiation
title_short Two-Pore-Domain Potassium Channel TREK–1 Mediates Pulmonary Fibrosis through Macrophage M2 Polarization and by Direct Promotion of Fibroblast Differentiation
title_sort two-pore-domain potassium channel trek–1 mediates pulmonary fibrosis through macrophage m2 polarization and by direct promotion of fibroblast differentiation
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10215911/
https://www.ncbi.nlm.nih.gov/pubmed/37238950
http://dx.doi.org/10.3390/biomedicines11051279
work_keys_str_mv AT zhangyunna twoporedomainpotassiumchanneltrek1mediatespulmonaryfibrosisthroughmacrophagem2polarizationandbydirectpromotionoffibroblastdifferentiation
AT fujiafeng twoporedomainpotassiumchanneltrek1mediatespulmonaryfibrosisthroughmacrophagem2polarizationandbydirectpromotionoffibroblastdifferentiation
AT hanyang twoporedomainpotassiumchanneltrek1mediatespulmonaryfibrosisthroughmacrophagem2polarizationandbydirectpromotionoffibroblastdifferentiation
AT fengdandan twoporedomainpotassiumchanneltrek1mediatespulmonaryfibrosisthroughmacrophagem2polarizationandbydirectpromotionoffibroblastdifferentiation
AT yueshaojie twoporedomainpotassiumchanneltrek1mediatespulmonaryfibrosisthroughmacrophagem2polarizationandbydirectpromotionoffibroblastdifferentiation
AT zhouyan twoporedomainpotassiumchanneltrek1mediatespulmonaryfibrosisthroughmacrophagem2polarizationandbydirectpromotionoffibroblastdifferentiation
AT luoziqiang twoporedomainpotassiumchanneltrek1mediatespulmonaryfibrosisthroughmacrophagem2polarizationandbydirectpromotionoffibroblastdifferentiation