Treatment with senicapoc, a K_Ca 3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome

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_Ca 3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS.

Experimental approach: K_Ca 3.1 channel knockout (Kccn4^-/- ) mice were exposed to ventilator-induced lung injury. Control mice exposed to ventilator-induced lung injury were treated with the K_Ca 3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO₂ /FiO₂ 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 PaO₂ /FiO₂ 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 PaO₂ /FiO₂ 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 PaO₂ /FiO₂ 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_Ca 3.1 channels and senicapoc improved the PaO₂ /FiO₂ 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_Ca 3.1 channels is a potential treatment in ARDS-like disease.