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

Tatiana Zyrianova; Benjamin Lopez; Riccardo Olcese; John Belperio; Christopher M. Waters; Leanne Wong; Victoria Nguyen; Sriharsha Talapaneni; Andreas Schwingshackl

doi:10.1038/s41598-020-78886-y

K_2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury

Tatiana Zyrianova
, Benjamin Lopez
, Riccardo Olcese
, John Belperio
, Christopher M. Waters
, Leanne Wong
, Victoria Nguyen
, Sriharsha Talapaneni
, Andreas Schwingshackl

Physiology

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

Abstract

No targeted therapies exist to counteract Hyperoxia (HO)-induced Acute Lung Injury (HALI). We previously found that HO downregulates alveolar K_2P2.1 (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 (Ca_V) 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 Ca_V inhibition. Therefore, Em stabilization with TREK-1 activators may represent a novel approach to counteract HALI.

Original language	English
Article number	22011
Journal	Scientific Reports
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41598-020-78886-y
State	Published - Dec 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

Funding

We thank Dr. Michela Ottolia (UCLA) and her lab for ongoing discussions and their intellectual input. We also thank Dr. Daniel Minor (UCSF) for providing us with the ML335 compound and for sharing with us his knowledge about the pharmacokinetics and pharmacodynamics of the compound. This study was supported by the following Grants: NIH HL118118-3 (AS); NIH HL131526 (CMW); NIH HL134346 (RO).

Funders	Funder number
National Institutes of Health (NIH)	HL134346, HL118118-3
National Heart, Lung, and Blood Institute (NHLBI)	R01HL131526
Office of Extramural Research, National Institutes of Health
Office of Research Infrastructure Programs, National Institutes of Health

ASJC Scopus subject areas

General

Access to Document

10.1038/s41598-020-78886-y

Cite this

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title = "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 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.",

author = "Tatiana Zyrianova and Benjamin Lopez and Riccardo Olcese and John Belperio and Waters, \{Christopher M.\} and Leanne Wong and Victoria Nguyen and Sriharsha Talapaneni and Andreas Schwingshackl",

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AU - Belperio, John

AU - Waters, Christopher M.

AU - Wong, Leanne

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AU - Talapaneni, Sriharsha

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