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Treatment with senicapoc in a porcine model of acute respiratory distress syndrome

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Treatment with senicapoc in a porcine model of acute respiratory distress syndrome. / Petersen, Asbjørn G; Lind, Peter C; Jensen, Anne-Sophie B; Eggertsen, Mark A; Granfeldt, Asger; Simonsen, Ulf.

I: Intensive Care Medicine Experimental, Bind 9, 20, 04.2021.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

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@article{eeb8a58de6fb4818a2f30906dab01fd4,
title = "Treatment with senicapoc in a porcine model of acute respiratory distress syndrome",
abstract = "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.",
author = "Petersen, {Asbj{\o}rn G} and Lind, {Peter C} and Jensen, {Anne-Sophie B} and Eggertsen, {Mark A} and Asger Granfeldt and Ulf Simonsen",
year = "2021",
month = apr,
doi = "10.1186/s40635-021-00381-z",
language = "English",
volume = "9",
journal = "Intensive Care Medicine Experimental",
issn = "2197-425X",
publisher = "SpringerOpen",

}

RIS

TY - JOUR

T1 - Treatment with senicapoc in a porcine model of acute respiratory distress syndrome

AU - Petersen, Asbjørn G

AU - Lind, Peter C

AU - Jensen, Anne-Sophie B

AU - Eggertsen, Mark A

AU - Granfeldt, Asger

AU - Simonsen, Ulf

PY - 2021/4

Y1 - 2021/4

N2 - 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.

AB - 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.

U2 - 10.1186/s40635-021-00381-z

DO - 10.1186/s40635-021-00381-z

M3 - Journal article

C2 - 33870468

VL - 9

JO - Intensive Care Medicine Experimental

JF - Intensive Care Medicine Experimental

SN - 2197-425X

M1 - 20

ER -