K(Ca)3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma.
<h4>Background</h4>The Ca(2+)-activated K(+) channel K(Ca)3.1 is expressed in several structural and inflammatory airway cell types and is proposed to play an important role in the pathophysiology of asthma. The aim of the current study was to determine whether inhibition of K(Ca)3.1 mod...
Saved in:
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0066886&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832586176386564096 |
|---|---|
| author | Joanne Van Der Velden Grace Sum Donna Barker Emmanuel Koumoundouros Garry Barcham Heike Wulff Neil Castle Peter Bradding Kenneth Snibson |
| author_facet | Joanne Van Der Velden Grace Sum Donna Barker Emmanuel Koumoundouros Garry Barcham Heike Wulff Neil Castle Peter Bradding Kenneth Snibson |
| author_sort | Joanne Van Der Velden |
| collection | DOAJ |
| description | <h4>Background</h4>The Ca(2+)-activated K(+) channel K(Ca)3.1 is expressed in several structural and inflammatory airway cell types and is proposed to play an important role in the pathophysiology of asthma. The aim of the current study was to determine whether inhibition of K(Ca)3.1 modifies experimental asthma in sheep.<h4>Methodology and principal findings</h4>Atopic sheep were administered either 30 mg/kg Senicapoc (ICA-17073), a selective inhibitor of the K(Ca)3.1-channel, or vehicle alone (0.5% methylcellulose) twice daily (orally). Both groups received fortnightly aerosol challenges with house dust mite allergen for fourteen weeks. A separate sheep group received no allergen challenges or drug treatment. In the vehicle-control group, twelve weeks of allergen challenges resulted in a 60±19% increase in resting airway resistance, and this was completely attenuated by treatment with Senicapoc (0.25±12%; n = 10, P = 0.0147). The vehicle-control group had a peak-early phase increase in lung resistance of 82±21%, and this was reduced by 58% with Senicapoc treatment (24±14%; n = 10, P = 0.0288). Senicapoc-treated sheep also demonstrated reduced airway hyperresponsiveness, requiring a significantly higher dose of carbachol to increase resistance by 100% compared to allergen-challenged vehicle-control sheep (20±5 vs. 52±18 breath-units of carbachol; n = 10, P = 0.0340). Senicapoc also significantly reduced eosinophil numbers in bronchoalveolar lavage taken 48 hours post-allergen challenge, and reduced vascular remodelling.<h4>Conclusions</h4>These findings suggest that K(Ca)3.1-activity contributes to allergen-induced airway responses, inflammation and vascular remodelling in a sheep model of asthma, and that inhibition of K(Ca)3.1 may be an effective strategy for blocking allergen-induced airway inflammation and hyperresponsiveness in humans. |
| format | Article |
| id | doaj-art-166f1f742d664833a977cb79776a9bb1 |
| institution | Kabale University |
| issn | 1932-6203 |
| language | English |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj-art-166f1f742d664833a977cb79776a9bb12025-01-26T05:31:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-0186e6688610.1371/journal.pone.0066886K(Ca)3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma.Joanne Van Der VeldenGrace SumDonna BarkerEmmanuel KoumoundourosGarry BarchamHeike WulffNeil CastlePeter BraddingKenneth Snibson<h4>Background</h4>The Ca(2+)-activated K(+) channel K(Ca)3.1 is expressed in several structural and inflammatory airway cell types and is proposed to play an important role in the pathophysiology of asthma. The aim of the current study was to determine whether inhibition of K(Ca)3.1 modifies experimental asthma in sheep.<h4>Methodology and principal findings</h4>Atopic sheep were administered either 30 mg/kg Senicapoc (ICA-17073), a selective inhibitor of the K(Ca)3.1-channel, or vehicle alone (0.5% methylcellulose) twice daily (orally). Both groups received fortnightly aerosol challenges with house dust mite allergen for fourteen weeks. A separate sheep group received no allergen challenges or drug treatment. In the vehicle-control group, twelve weeks of allergen challenges resulted in a 60±19% increase in resting airway resistance, and this was completely attenuated by treatment with Senicapoc (0.25±12%; n = 10, P = 0.0147). The vehicle-control group had a peak-early phase increase in lung resistance of 82±21%, and this was reduced by 58% with Senicapoc treatment (24±14%; n = 10, P = 0.0288). Senicapoc-treated sheep also demonstrated reduced airway hyperresponsiveness, requiring a significantly higher dose of carbachol to increase resistance by 100% compared to allergen-challenged vehicle-control sheep (20±5 vs. 52±18 breath-units of carbachol; n = 10, P = 0.0340). Senicapoc also significantly reduced eosinophil numbers in bronchoalveolar lavage taken 48 hours post-allergen challenge, and reduced vascular remodelling.<h4>Conclusions</h4>These findings suggest that K(Ca)3.1-activity contributes to allergen-induced airway responses, inflammation and vascular remodelling in a sheep model of asthma, and that inhibition of K(Ca)3.1 may be an effective strategy for blocking allergen-induced airway inflammation and hyperresponsiveness in humans.https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0066886&type=printable |
| spellingShingle | Joanne Van Der Velden Grace Sum Donna Barker Emmanuel Koumoundouros Garry Barcham Heike Wulff Neil Castle Peter Bradding Kenneth Snibson K(Ca)3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma. PLoS ONE |
| title | K(Ca)3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma. |
| title_full | K(Ca)3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma. |
| title_fullStr | K(Ca)3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma. |
| title_full_unstemmed | K(Ca)3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma. |
| title_short | K(Ca)3.1 channel-blockade attenuates airway pathophysiology in a sheep model of chronic asthma. |
| title_sort | k ca 3 1 channel blockade attenuates airway pathophysiology in a sheep model of chronic asthma |
| url | https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0066886&type=printable |
| work_keys_str_mv | AT joannevandervelden kca31channelblockadeattenuatesairwaypathophysiologyinasheepmodelofchronicasthma AT gracesum kca31channelblockadeattenuatesairwaypathophysiologyinasheepmodelofchronicasthma AT donnabarker kca31channelblockadeattenuatesairwaypathophysiologyinasheepmodelofchronicasthma AT emmanuelkoumoundouros kca31channelblockadeattenuatesairwaypathophysiologyinasheepmodelofchronicasthma AT garrybarcham kca31channelblockadeattenuatesairwaypathophysiologyinasheepmodelofchronicasthma AT heikewulff kca31channelblockadeattenuatesairwaypathophysiologyinasheepmodelofchronicasthma AT neilcastle kca31channelblockadeattenuatesairwaypathophysiologyinasheepmodelofchronicasthma AT peterbradding kca31channelblockadeattenuatesairwaypathophysiologyinasheepmodelofchronicasthma AT kennethsnibson kca31channelblockadeattenuatesairwaypathophysiologyinasheepmodelofchronicasthma |