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

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

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.

Original languageEnglish
Article number22011
JournalScientific Reports
Volume10
Issue number1
DOIs
StatePublished - Dec 2020

Bibliographical note

Funding Information:
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).

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

ASJC Scopus subject areas

  • General

Fingerprint

Dive into the research topics of 'K2P2.1 (TREK-1) potassium channel activation protects against hyperoxia-induced lung injury'. Together they form a unique fingerprint.

Cite this