Treatment with senicapoc in a porcine model of acute respiratory distress syndrome

Intensive Care Medicine Experimental

Anne-Sophie B. Jensen¹  Peter C. Lind¹  Ulf Simonsen¹  Asbjørn G. Petersen¹  Mark A. Eggertsen¹  Asger Granfeldt² 

[1] Department of Biomedicine, Aarhus University, Aarhus, Denmark;Department of Clinical Medicine, Anesthesiology, Aarhus University Hospital, Aarhus, Denmark;Department of Intensive Care, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99 G304, 8200, Aarhus, Denmark;

关键词: Acute respiratory distress syndrome;    Calcium-activated potassium channels of intermediate conductance;    Senicapoc;    Pig;   

DOI  :  10.1186/s40635-021-00381-z

来源: Springer

【 摘 要 】

BackgroundSenicapoc is a potent and selective blocker of KCa3.1, a calcium-activated potassium channel of intermediate conductance. In the present study, we investigated whether there is a beneficial effect of senicapoc in a large animal model of acute respiratory distress syndrome (ARDS). The primary end point was the PaO2/FiO2 ratio.MethodsARDS was induced in female pigs (42–49 kg) by repeated lung lavages followed by injurious mechanical ventilation. Animals were then randomly assigned to vehicle (n = 9) or intravenous senicapoc (10 mg, n = 9) and received lung-protective ventilation for 6 h.ResultsFinal senicapoc plasma concentrations were 67 ± 18 nM (n = 9). Senicapoc failed to change the primary endpoint PaO2/FiO2 ratio (senicapoc, 133 ± 23 mmHg; vehicle, 149 ± 68 mmHg). Lung compliance remained similar in the two groups. Senicapoc reduced the level of white blood cells and neutrophils, while the proinflammatory cytokines TNFα, IL-1β, and IL-6 in the bronchoalveolar lavage fluid were unaltered 6 h after induction of the lung injury. Senicapoc-treatment reduced the level of neutrophils in the alveolar space but with no difference between groups in the cumulative lung injury score. Histological analysis of pulmonary hemorrhage indicated a positive effect of senicapoc on alveolar–capillary barrier function, but this was not supported by measurements of albumin content and total protein in the bronchoalveolar lavage fluid.ConclusionsIn summary, senicapoc failed to improve the primary endpoint PaO2/FiO2 ratio, but reduced pulmonary hemorrhage and the influx of neutrophils into the lung. These findings open the perspective that blocking KCa3.1 channels is a potential treatment to reduce alveolar neutrophil accumulation and improve long-term outcome in ARDS.

【 授权许可】

CC BY