K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

Abstract No targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K2P2.1 (TREK-1) K+ channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmaco...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Tatiana Zyrianova, Benjamin Lopez, Riccardo Olcese, John Belperio, Christopher M. Waters, Leanne Wong, Victoria Nguyen, Sriharsha Talapaneni, Andreas Schwingshackl
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1ea20aed45944a3c87c2a1513b6b7521
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:1ea20aed45944a3c87c2a1513b6b7521
record_format	dspace
spelling	oai:doaj.org-article:1ea20aed45944a3c87c2a1513b6b75212021-12-02T12:40:41ZK2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury10.1038/s41598-020-78886-y2045-2322https://doaj.org/article/1ea20aed45944a3c87c2a1513b6b75212020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78886-yhttps://doaj.org/toc/2045-2322Abstract No targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K2P2.1 (TREK-1) K+ channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmacological intervention. Therefore, we hypothesized that TREK-1 activation protects against HALI. We treated HO-exposed mice and primary alveolar epithelial cells (AECs) with the novel TREK-1 activators ML335 and BL1249, and quantified physiological, histological, and biochemical lung injury markers. We determined the effects of these drugs on epithelial TREK-1 currents, plasma membrane potential (Em), and intracellular Ca2+ (iCa) concentrations using fluorometric assays, and blocked voltage-gated Ca2+ channels (CaV) as a downstream mechanism of cytokine secretion. Once-daily, intra-tracheal injections of HO-exposed mice with ML335 or BL1249 improved lung compliance, histological lung injury scores, broncho-alveolar lavage protein levels and cell counts, and IL-6 and IP-10 concentrations. TREK-1 activation also decreased IL-6, IP-10, and CCL-2 secretion from primary AECs. Mechanistically, ML335 and BL1249 induced TREK-1 currents in AECs, counteracted HO-induced cell depolarization, and lowered iCa2+ concentrations. In addition, CCL-2 secretion was decreased after L-type CaV inhibition. Therefore, Em stabilization with TREK-1 activators may represent a novel approach to counteract HALI.Tatiana ZyrianovaBenjamin LopezRiccardo OlceseJohn BelperioChristopher M. WatersLeanne WongVictoria NguyenSriharsha TalapaneniAndreas SchwingshacklNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-16 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tatiana Zyrianova Benjamin Lopez Riccardo Olcese John Belperio Christopher M. Waters Leanne Wong Victoria Nguyen Sriharsha Talapaneni Andreas Schwingshackl K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury
description	Abstract No targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K2P2.1 (TREK-1) K+ channels, which results in worsening lung injury. This decrease in TREK-1 levels leaves a subset of channels amendable to pharmacological intervention. Therefore, we hypothesized that TREK-1 activation protects against HALI. We treated HO-exposed mice and primary alveolar epithelial cells (AECs) with the novel TREK-1 activators ML335 and BL1249, and quantified physiological, histological, and biochemical lung injury markers. We determined the effects of these drugs on epithelial TREK-1 currents, plasma membrane potential (Em), and intracellular Ca2+ (iCa) concentrations using fluorometric assays, and blocked voltage-gated Ca2+ channels (CaV) as a downstream mechanism of cytokine secretion. Once-daily, intra-tracheal injections of HO-exposed mice with ML335 or BL1249 improved lung compliance, histological lung injury scores, broncho-alveolar lavage protein levels and cell counts, and IL-6 and IP-10 concentrations. TREK-1 activation also decreased IL-6, IP-10, and CCL-2 secretion from primary AECs. Mechanistically, ML335 and BL1249 induced TREK-1 currents in AECs, counteracted HO-induced cell depolarization, and lowered iCa2+ concentrations. In addition, CCL-2 secretion was decreased after L-type CaV inhibition. Therefore, Em stabilization with TREK-1 activators may represent a novel approach to counteract HALI.
format	article
author	Tatiana Zyrianova Benjamin Lopez Riccardo Olcese John Belperio Christopher M. Waters Leanne Wong Victoria Nguyen Sriharsha Talapaneni Andreas Schwingshackl
author_facet	Tatiana Zyrianova Benjamin Lopez Riccardo Olcese John Belperio Christopher M. Waters Leanne Wong Victoria Nguyen Sriharsha Talapaneni Andreas Schwingshackl
author_sort	Tatiana Zyrianova
title	K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury
title_short	K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury
title_full	K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury
title_fullStr	K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury
title_full_unstemmed	K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury
title_sort	k2p2.1 (trek-1) potassium channel activation protects against hyperoxia-induced lung injury
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/1ea20aed45944a3c87c2a1513b6b7521
work_keys_str_mv	AT tatianazyrianova k2p21trek1potassiumchannelactivationprotectsagainsthyperoxiainducedlunginjury AT benjaminlopez k2p21trek1potassiumchannelactivationprotectsagainsthyperoxiainducedlunginjury AT riccardoolcese k2p21trek1potassiumchannelactivationprotectsagainsthyperoxiainducedlunginjury AT johnbelperio k2p21trek1potassiumchannelactivationprotectsagainsthyperoxiainducedlunginjury AT christophermwaters k2p21trek1potassiumchannelactivationprotectsagainsthyperoxiainducedlunginjury AT leannewong k2p21trek1potassiumchannelactivationprotectsagainsthyperoxiainducedlunginjury AT victorianguyen k2p21trek1potassiumchannelactivationprotectsagainsthyperoxiainducedlunginjury AT sriharshatalapaneni k2p21trek1potassiumchannelactivationprotectsagainsthyperoxiainducedlunginjury AT andreasschwingshackl k2p21trek1potassiumchannelactivationprotectsagainsthyperoxiainducedlunginjury
_version_	1718393727648530432

K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

Ejemplares similares