Anti-inflammatory and anti-remodelling effects of ISU201, a modified form of the extracellular domain of human BST2, in experimental models of asthma: association with inhibition of histone acetylation.

There are few alternatives to glucocorticosteroids for treatment of asthma. We assessed the activity of a novel protein drug designated ISU201, the extracellular domain of the human cell surface protein BST2, stabilised by fusion with the Fc region of IgG, in mouse models of mild chronic asthma and...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Cristan Herbert, Alexander M Shadie, Melissa M Bunting, Nicodemus Tedla, Linda Garthwaite, Araluen Freeman, Hyouna Yoo, Sang-Ho Park, Rakesh K Kumar
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/18d5aa64280344d8a69f6cfe60f8dce1
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:18d5aa64280344d8a69f6cfe60f8dce1
record_format	dspace
spelling	oai:doaj.org-article:18d5aa64280344d8a69f6cfe60f8dce12021-11-18T08:30:05ZAnti-inflammatory and anti-remodelling effects of ISU201, a modified form of the extracellular domain of human BST2, in experimental models of asthma: association with inhibition of histone acetylation.1932-620310.1371/journal.pone.0090436https://doaj.org/article/18d5aa64280344d8a69f6cfe60f8dce12014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24594933/?tool=EBIhttps://doaj.org/toc/1932-6203There are few alternatives to glucocorticosteroids for treatment of asthma. We assessed the activity of a novel protein drug designated ISU201, the extracellular domain of the human cell surface protein BST2, stabilised by fusion with the Fc region of IgG, in mouse models of mild chronic asthma and an acute exacerbation of asthma. The ability of ISU201 to suppress airway inflammation and remodelling was compared with that of dexamethasone. Female BALB/c mice were systemically sensitised with ovalbumin, then received controlled low-level challenge with aerosolised ovalbumin for 6 weeks, which induced lesions of mild chronic asthma, and were treated with drugs during the final 2 weeks. Alternatively, sensitised mice received 4 weeks of chronic low-level challenge and were treated 24 and 2 hours before a final single moderate-level challenge, which triggered acute airway inflammation simulating an asthmatic exacerbation. Inflammation and remodelling were quantified, as was the expression of pro-inflammatory cytokines in bronchoalveolar lavage fluid and tissues. To identify cellular targets of ISU201, we assessed the effects of the drug on activated lymphocytes, macrophages and airway epithelial cells. In the model of mild chronic asthma, ISU201 was as effective as dexamethasone in suppressing airway inflammation and most changes of remodelling. In the model of an allergen-induced acute exacerbation of chronic asthma, ISU201 was also an effective anti-inflammatory agent, although it was less active than dexamethasone. The drug acted on multiple cellular targets, suppressing production of pro-inflammatory cytokines by lymphocytes and macrophages. ISU201 significantly reduced acetylation of histone H4 in airway epithelial cells, suggesting at least one potential mechanism of action. We conclude that in these models of asthma, ISU201 is a broad-spectrum inhibitor of both airway inflammation and remodelling. Thus, unlike drugs which target specific mediators, it could potentially be an alternative or an adjunct to glucocorticoids for the treatment of asthma.Cristan HerbertAlexander M ShadieMelissa M BuntingNicodemus TedlaLinda GarthwaiteAraluen FreemanHyouna YooSang-Ho ParkRakesh K KumarPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 3, p e90436 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Cristan Herbert Alexander M Shadie Melissa M Bunting Nicodemus Tedla Linda Garthwaite Araluen Freeman Hyouna Yoo Sang-Ho Park Rakesh K Kumar Anti-inflammatory and anti-remodelling effects of ISU201, a modified form of the extracellular domain of human BST2, in experimental models of asthma: association with inhibition of histone acetylation.
description	There are few alternatives to glucocorticosteroids for treatment of asthma. We assessed the activity of a novel protein drug designated ISU201, the extracellular domain of the human cell surface protein BST2, stabilised by fusion with the Fc region of IgG, in mouse models of mild chronic asthma and an acute exacerbation of asthma. The ability of ISU201 to suppress airway inflammation and remodelling was compared with that of dexamethasone. Female BALB/c mice were systemically sensitised with ovalbumin, then received controlled low-level challenge with aerosolised ovalbumin for 6 weeks, which induced lesions of mild chronic asthma, and were treated with drugs during the final 2 weeks. Alternatively, sensitised mice received 4 weeks of chronic low-level challenge and were treated 24 and 2 hours before a final single moderate-level challenge, which triggered acute airway inflammation simulating an asthmatic exacerbation. Inflammation and remodelling were quantified, as was the expression of pro-inflammatory cytokines in bronchoalveolar lavage fluid and tissues. To identify cellular targets of ISU201, we assessed the effects of the drug on activated lymphocytes, macrophages and airway epithelial cells. In the model of mild chronic asthma, ISU201 was as effective as dexamethasone in suppressing airway inflammation and most changes of remodelling. In the model of an allergen-induced acute exacerbation of chronic asthma, ISU201 was also an effective anti-inflammatory agent, although it was less active than dexamethasone. The drug acted on multiple cellular targets, suppressing production of pro-inflammatory cytokines by lymphocytes and macrophages. ISU201 significantly reduced acetylation of histone H4 in airway epithelial cells, suggesting at least one potential mechanism of action. We conclude that in these models of asthma, ISU201 is a broad-spectrum inhibitor of both airway inflammation and remodelling. Thus, unlike drugs which target specific mediators, it could potentially be an alternative or an adjunct to glucocorticoids for the treatment of asthma.
format	article
author	Cristan Herbert Alexander M Shadie Melissa M Bunting Nicodemus Tedla Linda Garthwaite Araluen Freeman Hyouna Yoo Sang-Ho Park Rakesh K Kumar
author_facet	Cristan Herbert Alexander M Shadie Melissa M Bunting Nicodemus Tedla Linda Garthwaite Araluen Freeman Hyouna Yoo Sang-Ho Park Rakesh K Kumar
author_sort	Cristan Herbert
title	Anti-inflammatory and anti-remodelling effects of ISU201, a modified form of the extracellular domain of human BST2, in experimental models of asthma: association with inhibition of histone acetylation.
title_short	Anti-inflammatory and anti-remodelling effects of ISU201, a modified form of the extracellular domain of human BST2, in experimental models of asthma: association with inhibition of histone acetylation.
title_full	Anti-inflammatory and anti-remodelling effects of ISU201, a modified form of the extracellular domain of human BST2, in experimental models of asthma: association with inhibition of histone acetylation.
title_fullStr	Anti-inflammatory and anti-remodelling effects of ISU201, a modified form of the extracellular domain of human BST2, in experimental models of asthma: association with inhibition of histone acetylation.
title_full_unstemmed	Anti-inflammatory and anti-remodelling effects of ISU201, a modified form of the extracellular domain of human BST2, in experimental models of asthma: association with inhibition of histone acetylation.
title_sort	anti-inflammatory and anti-remodelling effects of isu201, a modified form of the extracellular domain of human bst2, in experimental models of asthma: association with inhibition of histone acetylation.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/18d5aa64280344d8a69f6cfe60f8dce1
work_keys_str_mv	AT cristanherbert antiinflammatoryandantiremodellingeffectsofisu201amodifiedformoftheextracellulardomainofhumanbst2inexperimentalmodelsofasthmaassociationwithinhibitionofhistoneacetylation AT alexandermshadie antiinflammatoryandantiremodellingeffectsofisu201amodifiedformoftheextracellulardomainofhumanbst2inexperimentalmodelsofasthmaassociationwithinhibitionofhistoneacetylation AT melissambunting antiinflammatoryandantiremodellingeffectsofisu201amodifiedformoftheextracellulardomainofhumanbst2inexperimentalmodelsofasthmaassociationwithinhibitionofhistoneacetylation AT nicodemustedla antiinflammatoryandantiremodellingeffectsofisu201amodifiedformoftheextracellulardomainofhumanbst2inexperimentalmodelsofasthmaassociationwithinhibitionofhistoneacetylation AT lindagarthwaite antiinflammatoryandantiremodellingeffectsofisu201amodifiedformoftheextracellulardomainofhumanbst2inexperimentalmodelsofasthmaassociationwithinhibitionofhistoneacetylation AT araluenfreeman antiinflammatoryandantiremodellingeffectsofisu201amodifiedformoftheextracellulardomainofhumanbst2inexperimentalmodelsofasthmaassociationwithinhibitionofhistoneacetylation AT hyounayoo antiinflammatoryandantiremodellingeffectsofisu201amodifiedformoftheextracellulardomainofhumanbst2inexperimentalmodelsofasthmaassociationwithinhibitionofhistoneacetylation AT sanghopark antiinflammatoryandantiremodellingeffectsofisu201amodifiedformoftheextracellulardomainofhumanbst2inexperimentalmodelsofasthmaassociationwithinhibitionofhistoneacetylation AT rakeshkkumar antiinflammatoryandantiremodellingeffectsofisu201amodifiedformoftheextracellulardomainofhumanbst2inexperimentalmodelsofasthmaassociationwithinhibitionofhistoneacetylation
_version_	1718421668554080256

Anti-inflammatory and anti-remodelling effects of ISU201, a modified form of the extracellular domain of human BST2, in experimental models of asthma: association with inhibition of histone acetylation.

Ejemplares similares