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- Title
Specific Inhibition of Orai1-mediated Calcium Signalling Resolves Inflammation and Clears Bacteria in an Acute Respiratory Distress Syndrome Model.
- Authors
Ahmad, Saira; Wrennall, Joe A.; Goriounova, Alexandra S.; Sekhri, Malika; Iskarpatyoti, Jason A.; Ghosh, Arunava; Abdelwahab, Sabri H.; Voeller, Alexis; Rai, Mani; Mahida, Rahul Y.; Krajewski, Krzysztof; Ignar, Diane M.; Greenbaum, Alon; Moran, Timothy P.; Tilley, Stephen L.; Thickett, David R.; Sassano, M. Flori; Tarran, Robert
- Abstract
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.
- Subjects
ADULT respiratory distress syndrome; MICROCOCCACEAE; KLEBSIELLA pneumoniae; OXACILLIN; LIPOXINS; ALVEOLAR macrophages; INFLAMMATION; DRUG resistance in bacteria
- Publication
American Journal of Respiratory & Critical Care Medicine, 2024, Vol 209, Issue 6, p703
- ISSN
1073-449X
- Publication type
Article
- DOI
10.1164/rccm.202308-1393OC