tetano
Editor, Senior Moderator
Am J Physiol Lung Cell Mol Physiol
. 2022 Nov 21.
doi: 10.1152/ajplung.00116.2022. Online ahead of print.
Activation of TREK-1 (K[SUB]2P[/SUB]2.1) Potassium Channels Protects Against Influenza A-Induced Lung Injury
Tatiana Zyrianova[SUP] 1 [/SUP], Benjamin Lopez[SUP] 1 [/SUP], Kathlyn Zou[SUP] 1 [/SUP], Charles Gu[SUP] 1 [/SUP], Dayna Pham[SUP] 1 [/SUP], Sriharsha Talapaneni[SUP] 1 [/SUP], Christopher M Waters[SUP] 2 [/SUP], Riccardo Olcese[SUP] 3 4 [/SUP], Andreas Schwingshackl[SUP] 1 [/SUP]
Affiliations
Abstract
Influenza-A virus (IAV) infects yearly an estimated one billion people worldwide, resulting in 300,000-650,000 deaths. Preventive vaccination programs and antiviral medications represent the mainstay of therapy, but with unacceptably high morbidity and mortality rates new targeted therapeutic approaches are urgently needed. Since inflammatory processes are commonly associated with measurable changes in cell membrane potential (Em), we investigated whether Em hyperpolarization via TREK-1 (K[SUB]2P[/SUB]2.1) K[SUP]+[/SUP] channel activation can protect against influenza-A virus (IAV)-induced pneumonia. We infected mice with IAV, which after 5 days caused 5-15 % weight loss and a decrease in spontaneous activity, representing a clinically-relevant infection. We then started a three-day intra-tracheal treatment course with the novel TREK-1 activating compounds BL1249 or ML335. We confirmed TREK-1 activation with both compounds in untreated and IAV-infected primary human alveolar epithelial cells (HAEC) using high-throughput fluorescence-based FLIPR assays. In mice, TREK-1 activation with BL1249 and ML335 counteracted IAV-induced histological lung injury and loss in lung compliance, and improved BAL fluid total protein levels, cell counts, and inflammatory IL-6, IP-10/CXCL-10, MIP-1α, and TNF-α levels. To determine whether these anti-inflammatory effects were mediated by activation of alveolar epithelial TREK-1 channels, we studied the effects of BL1249 and ML335 in IAV-infected HAEC, and found that TREK-1 activation decreased IAV-induced inflammatory IL-6, IP-10/CXCL10, and CCL-2 secretion. Dissection of TREK-1 downstream signaling pathways and construction of protein-protein interaction (PPI) networks revealed NFκB1 and RIG-1 cascades as the most likely targets for TREK-1 protection. Therefore, TREK-1 activation may represent a novel therapeutic approach against IAV-induced lung injury.
Keywords: TREK-1 (KCNK2) ion channels; acute lung injury; cytokines; inflammation; influenza virus.
. 2022 Nov 21.
doi: 10.1152/ajplung.00116.2022. Online ahead of print.
Activation of TREK-1 (K[SUB]2P[/SUB]2.1) Potassium Channels Protects Against Influenza A-Induced Lung Injury
Tatiana Zyrianova[SUP] 1 [/SUP], Benjamin Lopez[SUP] 1 [/SUP], Kathlyn Zou[SUP] 1 [/SUP], Charles Gu[SUP] 1 [/SUP], Dayna Pham[SUP] 1 [/SUP], Sriharsha Talapaneni[SUP] 1 [/SUP], Christopher M Waters[SUP] 2 [/SUP], Riccardo Olcese[SUP] 3 4 [/SUP], Andreas Schwingshackl[SUP] 1 [/SUP]
Affiliations
- PMID: 36410022
- DOI: 10.1152/ajplung.00116.2022
Abstract
Influenza-A virus (IAV) infects yearly an estimated one billion people worldwide, resulting in 300,000-650,000 deaths. Preventive vaccination programs and antiviral medications represent the mainstay of therapy, but with unacceptably high morbidity and mortality rates new targeted therapeutic approaches are urgently needed. Since inflammatory processes are commonly associated with measurable changes in cell membrane potential (Em), we investigated whether Em hyperpolarization via TREK-1 (K[SUB]2P[/SUB]2.1) K[SUP]+[/SUP] channel activation can protect against influenza-A virus (IAV)-induced pneumonia. We infected mice with IAV, which after 5 days caused 5-15 % weight loss and a decrease in spontaneous activity, representing a clinically-relevant infection. We then started a three-day intra-tracheal treatment course with the novel TREK-1 activating compounds BL1249 or ML335. We confirmed TREK-1 activation with both compounds in untreated and IAV-infected primary human alveolar epithelial cells (HAEC) using high-throughput fluorescence-based FLIPR assays. In mice, TREK-1 activation with BL1249 and ML335 counteracted IAV-induced histological lung injury and loss in lung compliance, and improved BAL fluid total protein levels, cell counts, and inflammatory IL-6, IP-10/CXCL-10, MIP-1α, and TNF-α levels. To determine whether these anti-inflammatory effects were mediated by activation of alveolar epithelial TREK-1 channels, we studied the effects of BL1249 and ML335 in IAV-infected HAEC, and found that TREK-1 activation decreased IAV-induced inflammatory IL-6, IP-10/CXCL10, and CCL-2 secretion. Dissection of TREK-1 downstream signaling pathways and construction of protein-protein interaction (PPI) networks revealed NFκB1 and RIG-1 cascades as the most likely targets for TREK-1 protection. Therefore, TREK-1 activation may represent a novel therapeutic approach against IAV-induced lung injury.
Keywords: TREK-1 (KCNK2) ion channels; acute lung injury; cytokines; inflammation; influenza virus.