K_2P2.1 (TREK-1) Potassium Channel Activation Protects against Hyperoxia-Induced Lung Injury

Authors

Tatiana Zyrianova, University of California, Los Angeles
Benjamin Lopez, University of California, Los Angeles
Riccardo Olcese, University of California, Los Angeles
John Belperio, University of California, Los Angeles
Christopher M. Waters, University of KentuckyFollow
Leanne Wong, University of California, Los Angeles
Victoria Nguyen, University of California, Los Angeles
Sriharsha Talapaneni, University of California, Los Angeles
Andreas Schwingshackl, University of California, Los Angeles

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.

Document Type

Article

Publication Date

12-15-2020

Notes/Citation Information

Published in Scientific Reports, v. 10, issue 1, article no. 22011.

© The Author(s) 2020

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit https://creativecommons.org/licenses/by/4.0/.

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41598-020-78886-y

Funding Information

This study was supported by the following Grants: NIH HL118118-3 (AS); NIH HL131526 (CMW); NIH HL134346 (RO).

Repository Citation

Zyrianova, Tatiana; Lopez, Benjamin; Olcese, Riccardo; Belperio, John; Waters, Christopher M.; Wong, Leanne; Nguyen, Victoria; Talapaneni, Sriharsha; and Schwingshackl, Andreas, "K_2P2.1 (TREK-1) Potassium Channel Activation Protects against Hyperoxia-Induced Lung Injury" (2020). Physiology Faculty Publications. 165.
https://uknowledge.uky.edu/physiology_facpub/165