Rationale: Acute respiratory distress syndrome (ARDS) has an unacceptably high mortality rate (35%) and is without effective therapy. Orai1 is a Ca2+ channel involved in store-operated Ca2+ entry (SOCE), a process that exquisitely regulates inflammation. Orai1 is considered a druggable target, but no Orai1-specific inhibitors exist to date. Objectives: To evaluate whether ELD607, a first-in-class Orai1 antagonist, can treat ARDS caused by bacterial pneumonia in preclinical models. Methods: ELD607 pharmacology was evaluated in HEK293T cells and freshly isolated immune cells from patients with ARDS. A murine acute lung injury model caused by bacterial pneumonia was then used: mice were infected with Pseudomonas aeruginosa, Staphylococcus aureus, methicillin-resistant S. aureus, or multidrug-resistant P. aeruginosa and then treated with ELD607 intranasally. Measurements and Main Results: ELD607 specifically inhibited SOCE in HEK293T cells with a half-maximal inhibitory concentration of 9 nM. ELD607 was stable in ARDS airway secretions and inhibited SOCE in ARDS immune cells. In vivo, inhaled ELD607 significantly reduced neutrophilia and improved survival. Surprisingly, Orai1 inhibition by ELD607 caused a significant reduction in lung bacteria, including methicillin-resistant S. aureus. ELD607 worked as an immunomodulator that reduced cytokine levels, reduced neutrophilia, and promoted macrophage-mediated resolution of inflammation and clearance of bacteria. Indeed, when alveolar macrophages were depleted with inhaled clodronate, ELD607 was no longer able to resolve inflammation or clear bacteria. Conclusions: These data indicate that specific Orai1 inhibition by ELD607 may be a novel approach to reduce multiorgan inflammation and treat antibiotic-resistant bacteria.

中文翻译：

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特异性抑制 Orai1 介导的钙信号传导可解决急性呼吸窘迫综合征模型中的炎症并清除细菌。


理由：急性呼吸窘迫综合征 (ARDS) 的死亡率高得令人无法接受 (35%)，并且没有有效的治疗方法。 Orai1 是一种 Ca2+ 通道，参与钙池操纵的 Ca2+ 进入 (SOCE)，这是一个精细调节炎症的过程。 Orai1 被认为是一个可药物靶标，但迄今为止尚不存在 Orai1 特异性抑制剂。目的：在临床前模型中评估首创Orai1拮抗剂ELD607是否可以治疗细菌性肺炎引起的ARDS。方法：在 HEK293T 细胞和来自 ARDS 患者的新鲜分离的免疫细胞中评估 ELD607 药理学。然后采用细菌性肺炎引起的小鼠急性肺损伤模型：小鼠感染铜绿假单胞菌、金黄色葡萄球菌、耐甲氧西林金黄色葡萄球菌或多重耐药铜绿假单胞菌，然后鼻内给予ELD607治疗。测量和主要结果：ELD607 特异性抑制 HEK293T 细胞中的 SOCE，半数抑制浓度为 9 nM。 ELD607 在 ARDS 气道分泌物中稳定，并抑制 ARDS 免疫细胞中的 SOCE。在体内，吸入 ELD607 显着减少中性粒细胞增多并提高生存率。令人惊讶的是，ELD607 抑制 Orai1 导致肺部细菌显着减少，包括耐甲氧西林金黄色葡萄球菌。 ELD607 作为一种免疫调节剂，可降低细胞因子水平，减少中性粒细胞增多，并促进巨噬细胞介导的炎症消退和细菌清除。事实上，当吸入氯膦酸盐耗尽肺泡巨噬细胞时，ELD607 不再能够解决炎症或清除细菌。结论：这些数据表明 ELD607 特异性抑制 Orai1 可能是减少多器官炎症和治疗抗生素耐药细菌的新方法。