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TREK-1 Potassium Channel Activation Protects Against Influenza-A Induced Lung Injury
American Journal of Respiratory and Critical Care Medicine ; 205(1), 2022.
Article in English | EMBASE | ID: covidwho-1927790
ABSTRACT
Introduction and Rationale No targeted therapies exist that improve the outcomes of patients with Acute Respiratory Distress Syndrome (ARDS), in part to the multifactorial etiology of this devastating disease. Infectious agents remain the most common initiating insults, and besides SARS-CoV-2, Influenza-A virus (IAV) is responsible for more ARDS cases and deaths than any other agent. In fact, IAV increases the risk of mortality in ARDS patients three-fold, and accounts for almost half of all ARDS deaths. We recently identified TREK-1 potassium channels on epithelial cells as important regulators of alveolar inflammation and barrier function, two hallmarks of ARDS, and found that pharmacological activation of TREK-1 protects against hyperoxia-induced lung injury. However, whether TREK-1 channels convey similar protection in a clinically more relevant IAVinduced lung injury model, remains unknown.

Methods:

We infected adult C57BL/6 wildtype mice intra-tracheally (i.t.) with IAV (PR8 strain;TCID50 400), followed by once-daily i.t. injections (days 5, 6 and 7 post-IAV) with the novel TREK-1 activating compounds ML335 (60mcg/kg), BL1249 (100mcg/kg), or a vehicle control, to create a clinically-relevant treatment model. To evaluate the role of epithelial cells in this model, we infected primary human alveolar epithelial cells (HAEC) with IAV (0.01 pfu) for 24 hours. Endpoint analysis consistent in quantification of quasi-static lung compliance;BAL fluid total protein, cell counts, and ROS concentrations;cytokine levels in BAL fluid and cell supernatants;and HAEC viability (XTT assay). In addition, we measured alterations in epithelial potassium currents (fluorometric FLIPR assays) and in IAV-induced signaling cascades (real-time PCR) following IAV infection and treatment with our TREK-1 activators.

Results:

Oncedaily treatment of mice with the TREK-1 activating compounds ML335 or BL1249 following IAV infection improved lung compliance, and BAL fluid total protein levels, cell counts, IL-6, CXCL-10, MIP-1alpha, and TNF-alpha concentrations, but not ROS, CCL-2 or IL-10 levels. In HAEC, TREK-1 activation improved IAV-induced IL-6, CXCL-10, and CCL-2 levels, while MIP-1alpha, TNF-alpha and IL-10 levels remained unchanged. XTT assays confirmed that in our model IAV infection did not cause significant cell death. Interestingly, IAV infection decreased HAEC potassium currents, which could be counteracted by TREK-1 activation and cell hyperpolarization. Finally, TREK-1 activationmediated cell hyperpolarization inhibited TLR4- and TNFSF13-mediated downstream signaling in IAV-infected HAEC, whereas NFkB, RIG1, TLR3, and TLR7 signaling was not affected.

Conclusions:

TREK-1 potassium channel activation may represent a novel approach to protect against IAV-induced acute lung injury.
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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: American Journal of Respiratory and Critical Care Medicine Year: 2022 Document Type: Article

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Full text: Available Collection: Databases of international organizations Database: EMBASE Language: English Journal: American Journal of Respiratory and Critical Care Medicine Year: 2022 Document Type: Article