Specific Inhibition of Orai1-mediated Calcium Signalling Resolves Inflammation and Clears Bacteria in an Acute Respiratory Distress Syndrome Model
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.
| Errataetall: |
CommentIn: Am J Respir Crit Care Med. 2024 Mar 15;209(6):623-625. - PMID 38064242 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:209 |
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| Enthalten in: |
American journal of respiratory and critical care medicine - 209(2024), 6 vom: 15. März, Seite 703-715 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ahmad, Saira [VerfasserIn] |
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| Links: |
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| Themen: |
ARDS |
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| Anmerkungen: |
Date Completed 18.03.2024 Date Revised 29.03.2024 published: Print CommentIn: Am J Respir Crit Care Med. 2024 Mar 15;209(6):623-625. - PMID 38064242 Citation Status MEDLINE |
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| doi: |
10.1164/rccm.202308-1393OC |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM364639199 |
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| 100 | 1 | |a Ahmad, Saira |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Specific Inhibition of Orai1-mediated Calcium Signalling Resolves Inflammation and Clears Bacteria in an Acute Respiratory Distress Syndrome Model |
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| 500 | |a Date Completed 18.03.2024 | ||
| 500 | |a Date Revised 29.03.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a CommentIn: Am J Respir Crit Care Med. 2024 Mar 15;209(6):623-625. - PMID 38064242 | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a ICRAC | |
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| 700 | 1 | |a Wrennall, Joe A |e verfasserin |4 aut | |
| 700 | 1 | |a Goriounova, Alexandra S |e verfasserin |4 aut | |
| 700 | 1 | |a Sekhri, Malika |e verfasserin |4 aut | |
| 700 | 1 | |a Iskarpatyoti, Jason A |e verfasserin |4 aut | |
| 700 | 1 | |a Ghosh, Arunava |e verfasserin |4 aut | |
| 700 | 1 | |a Abdelwahab, Sabri H |e verfasserin |4 aut | |
| 700 | 1 | |a Voeller, Alexis |e verfasserin |4 aut | |
| 700 | 1 | |a Rai, Mani |e verfasserin |4 aut | |
| 700 | 1 | |a Mahida, Rahul Y |e verfasserin |4 aut | |
| 700 | 1 | |a Krajewski, Krzysztof |e verfasserin |4 aut | |
| 700 | 1 | |a Ignar, Diane M |e verfasserin |4 aut | |
| 700 | 1 | |a Greenbaum, Alon |e verfasserin |4 aut | |
| 700 | 1 | |a Moran, Timothy P |e verfasserin |4 aut | |
| 700 | 1 | |a Tilley, Stephen L |e verfasserin |4 aut | |
| 700 | 1 | |a Thickett, David R |e verfasserin |4 aut | |
| 700 | 1 | |a Sassano, M Flori |e verfasserin |4 aut | |
| 700 | 1 | |a Tarran, Robert |e verfasserin |4 aut | |
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