1. Treatment with senicapoc, a K Ca 3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome
- Author
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Asbjørn Graver Petersen, Peter Carøe Lind, Asger Granfeldt, Anne-Sophie Bonde Jensen, Susie Mogensen, and Ulf Simonsen
- Subjects
medicine.medical_specialty ,ARDS ,Hypoxia/complications ,Lung/metabolism ,ICA-17043 ,Pulmonary compliance ,Lung injury ,Gastroenterology ,Hypoxemia ,Mice ,senicapoc ,Internal medicine ,GENETIC DEFICIT ,Acetamides ,medicine ,Animals ,ACTIVATED POTASSIUM CHANNELS ,mouse ,IN-VIVO ,HYPERPOLARIZING FACTOR ,Pharmacology ,Ventilator-Induced Lung Injury/metabolism ,Trityl Compounds/metabolism ,Lung ,TRPV4 CHANNELS ,K+ CHANNELS ,medicine.diagnostic_test ,business.industry ,ventilator-induced lung injury ,acute respiratory distress syndrome ,EDEMA ,respiratory system ,medicine.disease ,Respiratory Distress Syndrome/drug therapy ,respiratory tract diseases ,INDUCED LUNG INJURY ,Bronchoalveolar lavage ,medicine.anatomical_structure ,calcium-activated activated potassium channels of intermediate conductance ,Breathing ,Tumor necrosis factor alpha ,medicine.symptom ,business ,CL-SECRETION - 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.
- Published
- 2022