Treatment with senicapoc, a K
            Ca3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome

Asbjørn Petersen; Peter Carøe Lind; Susie Mogensen; Anne-Sophie Bonde Jensen; Asger Granfeldt; Ulf Simonsen

doi:10.1111/bph.15704

Treatment with senicapoc, a K _Ca3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome

Asbjørn Petersen, Peter Carøe Lind, Susie Mogensen, Anne-Sophie Bonde Jensen, Asger Granfeldt, Ulf Simonsen^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

6 Citationer (Scopus)

Abstract

Background and Purpose: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and severe hypoxaemia. We investigated whether genetic deficit or blockade of calcium-activated potassium (K _Ca3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS. Experimental Approach: K _Ca3.1 channel knockout (Kccn4 ^-/-) mice were exposed to ventilator-induced lung injury. Control mice exposed to ventilator-induced lung injury were treated with the K _Ca3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO ₂/FiO ₂ ratio), lung compliance, lung wet-to-dry weight and protein and cytokines in bronchoalveolar lavage fluid (BALF). Key Results: Ventilator-induced lung injury resulted in lung oedema, decreased lung compliance, a severe drop in PaO ₂/FiO ₂ ratio, increased protein, neutrophils and tumour necrosis factor-alpha (TNF-α) in BALF from wild-type mice compared with Kccn4 ^-/- mice. Pretreatment with senicapoc (10–70 mg·kg ⁻¹) prevented the reduction in PaO ₂/FiO ₂ ratio, decrease in lung compliance, increased protein and TNF-α. Senicapoc (30 mg·kg ⁻¹) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30 mg·kg ⁻¹ senicapoc also improved the PaO ₂/FiO ₂ ratio and reduced lung injury score and neutrophils in the BALF compared with vehicle-treated mice. In human lung epithelial cells, senicapoc decreased TNF-α-induced permeability. Conclusions and Implications: Genetic deficiency of K _Ca3.1 channels and senicapoc improved the PaO ₂/FiO ₂ ratio and decreased the cytokines after a ventilator-induced lung injury. Moreover, senicapoc directly affects lung epithelial cells and blocks neutrophil infiltration in the injured lung. These findings indicate that blocking K _Ca3.1 channels is a potential treatment in ARDS-like disease.

Originalsprog	Engelsk
Tidsskrift	British Journal of Pharmacology
Vol/bind	179
Nummer	10
Sider (fra-til)	2175-2192
Antal sider	18
ISSN	0007-1188
DOI	https://doi.org/10.1111/bph.15704
Status	Udgivet - maj 2022

Adgang til dokumentet

10.1111/bph.15704

Citationsformater

@article{f039b7ed5286468c81309493dff6f5fb,

title = "Treatment with senicapoc, a K Ca3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome",

abstract = "Background and Purpose: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and severe hypoxaemia. We investigated whether genetic deficit or blockade of calcium-activated potassium (K Ca3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS. Experimental Approach: K Ca3.1 channel knockout (Kccn4 -/-) mice were exposed to ventilator-induced lung injury. Control mice exposed to ventilator-induced lung injury were treated with the K Ca3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO 2/FiO 2 ratio), lung compliance, lung wet-to-dry weight and protein and cytokines in bronchoalveolar lavage fluid (BALF). Key Results: Ventilator-induced lung injury resulted in lung oedema, decreased lung compliance, a severe drop in PaO 2/FiO 2 ratio, increased protein, neutrophils and tumour necrosis factor-alpha (TNF-α) in BALF from wild-type mice compared with Kccn4 -/- mice. Pretreatment with senicapoc (10–70 mg·kg −1) prevented the reduction in PaO 2/FiO 2 ratio, decrease in lung compliance, increased protein and TNF-α. Senicapoc (30 mg·kg −1) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30 mg·kg −1 senicapoc also improved the PaO 2/FiO 2 ratio and reduced lung injury score and neutrophils in the BALF compared with vehicle-treated mice. In human lung epithelial cells, senicapoc decreased TNF-α-induced permeability. Conclusions and Implications: Genetic deficiency of K Ca3.1 channels and senicapoc improved the PaO 2/FiO 2 ratio and decreased the cytokines after a ventilator-induced lung injury. Moreover, senicapoc directly affects lung epithelial cells and blocks neutrophil infiltration in the injured lung. These findings indicate that blocking K Ca3.1 channels is a potential treatment in ARDS-like disease. ",

keywords = "acute respiratory distress syndrome, calcium-activated activated potassium channels of intermediate conductance, mouse, senicapoc, ventilator-induced lung injury, INDUCED LUNG INJURY, ACTIVATED POTASSIUM CHANNELS, HYPERPOLARIZING FACTOR, EDEMA, IN-VIVO, TRPV4 CHANNELS, CL-SECRETION, ICA-17043, K+ CHANNELS, GENETIC DEFICIT, Lung/metabolism, Hypoxia/complications, Animals, Ventilator-Induced Lung Injury/metabolism, Respiratory Distress Syndrome/drug therapy, Mice, Acetamides, Trityl Compounds/metabolism",

author = "Asbj{\o}rn Petersen and Lind, {Peter Car{\o}e} and Susie Mogensen and Jensen, {Anne-Sophie Bonde} and Asger Granfeldt and Ulf Simonsen",

year = "2022",

month = may,

doi = "10.1111/bph.15704",

language = "English",

volume = "179",

pages = "2175--2192",

journal = "British Journal of Pharmacology",

issn = "0007-1188",

publisher = "John Wiley & Sons Inc.",

number = "10",

}

Treatment with senicapoc, a K _Ca3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome. / Petersen, Asbjørn ; Lind, Peter Carøe ; Mogensen, Susie et al.
I: British Journal of Pharmacology, Bind 179, Nr. 10, 05.2022, s. 2175-2192.

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

TY - JOUR

T1 - Treatment with senicapoc, a K Ca3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome

AU - Petersen, Asbjørn

AU - Lind, Peter Carøe

AU - Mogensen, Susie

AU - Jensen, Anne-Sophie Bonde

AU - Granfeldt, Asger

AU - Simonsen, Ulf

PY - 2022/5

Y1 - 2022/5

N2 - Background and Purpose: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and severe hypoxaemia. We investigated whether genetic deficit or blockade of calcium-activated potassium (K Ca3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS. Experimental Approach: K Ca3.1 channel knockout (Kccn4 -/-) mice were exposed to ventilator-induced lung injury. Control mice exposed to ventilator-induced lung injury were treated with the K Ca3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO 2/FiO 2 ratio), lung compliance, lung wet-to-dry weight and protein and cytokines in bronchoalveolar lavage fluid (BALF). Key Results: Ventilator-induced lung injury resulted in lung oedema, decreased lung compliance, a severe drop in PaO 2/FiO 2 ratio, increased protein, neutrophils and tumour necrosis factor-alpha (TNF-α) in BALF from wild-type mice compared with Kccn4 -/- mice. Pretreatment with senicapoc (10–70 mg·kg −1) prevented the reduction in PaO 2/FiO 2 ratio, decrease in lung compliance, increased protein and TNF-α. Senicapoc (30 mg·kg −1) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30 mg·kg −1 senicapoc also improved the PaO 2/FiO 2 ratio and reduced lung injury score and neutrophils in the BALF compared with vehicle-treated mice. In human lung epithelial cells, senicapoc decreased TNF-α-induced permeability. Conclusions and Implications: Genetic deficiency of K Ca3.1 channels and senicapoc improved the PaO 2/FiO 2 ratio and decreased the cytokines after a ventilator-induced lung injury. Moreover, senicapoc directly affects lung epithelial cells and blocks neutrophil infiltration in the injured lung. These findings indicate that blocking K Ca3.1 channels is a potential treatment in ARDS-like disease.

AB - Background and Purpose: Acute respiratory distress syndrome (ARDS) is characterized by pulmonary oedema and severe hypoxaemia. We investigated whether genetic deficit or blockade of calcium-activated potassium (K Ca3.1) channels would counteract pulmonary oedema and hypoxaemia in ventilator-induced lung injury, an experimental model for ARDS. Experimental Approach: K Ca3.1 channel knockout (Kccn4 -/-) mice were exposed to ventilator-induced lung injury. Control mice exposed to ventilator-induced lung injury were treated with the K Ca3.1 channel inhibitor, senicapoc. The outcomes were oxygenation (PaO 2/FiO 2 ratio), lung compliance, lung wet-to-dry weight and protein and cytokines in bronchoalveolar lavage fluid (BALF). Key Results: Ventilator-induced lung injury resulted in lung oedema, decreased lung compliance, a severe drop in PaO 2/FiO 2 ratio, increased protein, neutrophils and tumour necrosis factor-alpha (TNF-α) in BALF from wild-type mice compared with Kccn4 -/- mice. Pretreatment with senicapoc (10–70 mg·kg −1) prevented the reduction in PaO 2/FiO 2 ratio, decrease in lung compliance, increased protein and TNF-α. Senicapoc (30 mg·kg −1) reduced histopathological lung injury score and neutrophils in BALF. After injurious ventilation, administration of 30 mg·kg −1 senicapoc also improved the PaO 2/FiO 2 ratio and reduced lung injury score and neutrophils in the BALF compared with vehicle-treated mice. In human lung epithelial cells, senicapoc decreased TNF-α-induced permeability. Conclusions and Implications: Genetic deficiency of K Ca3.1 channels and senicapoc improved the PaO 2/FiO 2 ratio and decreased the cytokines after a ventilator-induced lung injury. Moreover, senicapoc directly affects lung epithelial cells and blocks neutrophil infiltration in the injured lung. These findings indicate that blocking K Ca3.1 channels is a potential treatment in ARDS-like disease.

KW - acute respiratory distress syndrome

KW - calcium-activated activated potassium channels of intermediate conductance

KW - mouse

KW - senicapoc

KW - ventilator-induced lung injury

KW - INDUCED LUNG INJURY

KW - ACTIVATED POTASSIUM CHANNELS

KW - HYPERPOLARIZING FACTOR

KW - EDEMA

KW - IN-VIVO

KW - TRPV4 CHANNELS

KW - CL-SECRETION

KW - ICA-17043

KW - K+ CHANNELS

KW - GENETIC DEFICIT

KW - Lung/metabolism

KW - Hypoxia/complications

KW - Animals

KW - Ventilator-Induced Lung Injury/metabolism

KW - Respiratory Distress Syndrome/drug therapy

KW - Mice

KW - Acetamides

KW - Trityl Compounds/metabolism

U2 - 10.1111/bph.15704

DO - 10.1111/bph.15704

M3 - Journal article

C2 - 34623632

SN - 0007-1188

VL - 179

SP - 2175

EP - 2192

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 10

ER -

Treatment with senicapoc, a K Ca3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome

Abstract

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Citationsformater

Treatment with senicapoc, a K _Ca3.1 channel blocker, alleviates hypoxaemia in a mouse model of acute respiratory distress syndrome