Treatment with senicapoc, a K Ca3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome

Asbjørn Petersen, Peter Carøe Lind, Susie Mogensen, Anne-Sophie Bonde Jensen, Asger Granfeldt, Ulf Simonsen*

*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

6 Citations (Scopus)

Abstract

Background and Purpose: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and severe hypoxaemia. We investigated whether genetic deficit or blockade of calcium-activated potassium (K Ca3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS. Experimental Approach: K Ca3.1 channel knockout (Kccn4 -/-) mice were exposed to ventilator-induced lung injury. Control mice exposed to ventilator-induced lung injury were treated with the K Ca3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO 2/FiO 2 ratio), lung compliance, lung wet-to-dry weight and protein and cytokines in bronchoalveolar lavage fluid (BALF). Key Results: Ventilator-induced lung injury resulted in lung oedema, decreased lung compliance, a severe drop in PaO 2/FiO 2 ratio, increased protein, neutrophils and tumour necrosis factor-alpha (TNF-α) in BALF from wild-type mice compared with Kccn4 -/- mice. Pretreatment with senicapoc (10–70 mg·kg −1) prevented the reduction in PaO 2/FiO 2 ratio, decrease in lung compliance, increased protein and TNF-α. Senicapoc (30 mg·kg −1) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30 mg·kg −1 senicapoc also improved the PaO 2/FiO 2 ratio and reduced lung injury score and neutrophils in the BALF compared with vehicle-treated mice. In human lung epithelial cells, senicapoc decreased TNF-α-induced permeability. Conclusions and Implications: Genetic deficiency of K Ca3.1 channels and senicapoc improved the PaO 2/FiO 2 ratio and decreased the cytokines after a ventilator-induced lung injury. Moreover, senicapoc directly affects lung epithelial cells and blocks neutrophil infiltration in the injured lung. These findings indicate that blocking K Ca3.1 channels is a potential treatment in ARDS-like disease.

Original languageEnglish
JournalBritish Journal of Pharmacology
Volume179
Issue10
Pages (from-to)2175-2192
Number of pages18
ISSN0007-1188
DOIs
Publication statusPublished - May 2022

Keywords

  • acute respiratory distress syndrome
  • calcium-activated activated potassium channels of intermediate conductance
  • mouse
  • senicapoc
  • ventilator-induced lung injury
  • INDUCED LUNG INJURY
  • ACTIVATED POTASSIUM CHANNELS
  • HYPERPOLARIZING FACTOR
  • EDEMA
  • IN-VIVO
  • TRPV4 CHANNELS
  • CL-SECRETION
  • ICA-17043
  • K+ CHANNELS
  • GENETIC DEFICIT
  • Lung/metabolism
  • Hypoxia/complications
  • Animals
  • Ventilator-Induced Lung Injury/metabolism
  • Respiratory Distress Syndrome/drug therapy
  • Mice
  • Acetamides
  • Trityl Compounds/metabolism

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