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 to date, no Orai1-specific inhibitors exist. 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 ARDS patient immune cells. A murine acute lung injury model caused by bacterial pneumonia was then used. Mice were infected with P. aeruginosa, S. aureus, methicillin-resistant S. aureus (MRSA) or multidrug-resistant P. aeruginosa (MDR-Pa) and then treated with ELD607 intranasally. Measurements and Main Results: ELD607 specifically inhibited SOCE in HEK293T cells with an IC50 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 MRSA. ELD607 worked as an immunomodulator that reduced cytokine levels, lowered neutrophilia and promoted both 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 multi-organ 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 ARDS 模型中的炎症并清除细菌。

理由：急性呼吸窘迫综合征 (ARDS) 的死亡率高得令人难以接受 (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点，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 细胞和新鲜分离的 ARDS 患者免疫细胞中评估 ELD607 药理学。然后使用由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（MRSA）或多重耐药铜绿假单胞菌（MDR-Pa），然后用ELD607鼻内治疗。测量和主要结果：ELD607 特异性抑制 HEK293T 细胞中的 SOCE，IC50 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（包括 MRSA）显着减少。ELD607 作为一种免疫调节剂，可降低细胞因子水平、降低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。