Treatment with senicapoc in a porcine model of acute respiratory distress syndrome
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
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| Enthalten in: |
Intensive care medicine experimental - 9(2021), 1 vom: 19. Apr., Seite 20 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Petersen, Asbjørn G [VerfasserIn] |
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| Links: |
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| Themen: |
Acute respiratory distress syndrome |
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| Anmerkungen: |
Date Revised 22.04.2021 published: Electronic Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1186/s40635-021-00381-z |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM324251130 |
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| 520 | |a BACKGROUND: 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 | ||
| 520 | |a METHODS: 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 | ||
| 520 | |a RESULTS: 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 | ||
| 520 | |a CONCLUSIONS: 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Acute respiratory distress syndrome | |
| 650 | 4 | |a Calcium-activated potassium channels of intermediate conductance | |
| 650 | 4 | |a Pig | |
| 650 | 4 | |a Senicapoc | |
| 700 | 1 | |a Lind, Peter C |e verfasserin |4 aut | |
| 700 | 1 | |a Jensen, Anne-Sophie B |e verfasserin |4 aut | |
| 700 | 1 | |a Eggertsen, Mark A |e verfasserin |4 aut | |
| 700 | 1 | |a Granfeldt, Asger |e verfasserin |4 aut | |
| 700 | 1 | |a Simonsen, Ulf |e verfasserin |4 aut | |
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