Treatment with senicapoc, a K 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 3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS.

EXPERIMENTAL APPROACH

K 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 3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO /FiO 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 /FiO 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 ) prevented the reduction in PaO /FiO ratio, decrease in lung compliance, increased protein and TNF-α. Senicapoc (30 mg·kg ) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30 mg·kg senicapoc also improved the PaO /FiO 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 3.1 channels and senicapoc improved the PaO /FiO 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 3.1 channels is a potential treatment in ARDS-like disease.