| First Author | Petersen AG | Year | 2022 |
| Journal | Br J Pharmacol | Volume | 179 |
| Issue | 10 | Pages | 2175-2192 |
| PubMed ID | 34623632 | Mgi Jnum | J:349417 |
| Mgi Id | MGI:7647043 | Doi | 10.1111/bph.15704 |
| Citation | Petersen AG, et al. (2022) Treatment with senicapoc, a K(Ca) 3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome. Br J Pharmacol 179(10):2175-2192 |
| abstractText | 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 (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-alpha) 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-alpha. 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-alpha-induced permeability. CONCLUSIONS AND IMPLICATIONS: Genetic deficiency of K(Ca) 3.1 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(Ca) 3.1 channels is a potential treatment in ARDS-like disease. |
