Senicapoc 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. ARDS 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. Final 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. In 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.

中文翻译：

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赛尼卡波治疗急性呼吸窘迫综合征猪模型

Senicapoc是KCa3.1的有效和选择性阻滞剂，KCa3.1是中等电导的钙激活钾通道。在本研究中，我们调查了在大型急性呼吸窘迫综合征（ARDS）动物模型中塞尼卡波的有益作用。主要终点是PaO2 / FiO2比。雌性猪（42–49 kg）通过反复的肺灌洗并随后进行有害的机械通气诱发了ARDS。然后将动物随机分配至媒介物（n = 9）或静脉给予senicapoc（10 mg，n = 9），并进行肺保护通气6 h。最终的senicapoc血浆浓度为67±18 nM（n = 9）。Senicapoc无法更改主要终点PaO2 / FiO2比（senicapoc，133±23 mmHg；媒介物，149±68 mmHg）。两组的肺依从性保持相似。Senicapoc降低了白细胞和中性粒细胞的水平，而诱导肺损伤后6 h支气管肺泡灌洗液中的促炎细胞因子TNFα，IL-1β和IL-6保持不变。Senicapoc治疗可降低肺泡腔中性粒细胞的水平，但两组之间的累积肺损伤评分无差异。肺出血的组织学分析表明，塞尼卡波对肺泡-毛细血管屏障功能有积极作用，但测量支气管肺泡灌洗液中白蛋白含量和总蛋白并不支持这种作用。总之，senicapoc未能改善主要终点PaO2 / FiO2比率，但减少了肺出血和中性粒细胞向肺的流入。这些发现打开了阻断KCa3的观点。