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Route of administration affects corticosteroid sensitivity of a combined ovalbumin and lipopolysaccharide model of asthma exacerbation in guinea-pigs

Lowe, Alexander P. P., Thomas, Rhian S., Nials, Anthony T., Kidd, Emma J., Broadley, Kenneth J. and Ford, William R. 2017. Route of administration affects corticosteroid sensitivity of a combined ovalbumin and lipopolysaccharide model of asthma exacerbation in guinea-pigs. Journal of Pharmacology and Experimental Therapeutics 362 (2) , pp. 327-337. 10.1124/jpet.117.241927

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Abstract

Lipopolysaccharide (LPS) contributes to asthma exacerbations and development of inhaled corticosteroid insensitivity. Complete resistance to systemic corticosteroids is rare and most patients lie on a continuum of steroid responsiveness. The objective of this study was to examine the sensitivity of combined ovalbumin- (Ova) and LPS-induced functional and inflammatory responses to inhaled and systemic corticosteroid in conscious guinea-pigs, to test the hypothesis that the route of administration affects its sensitivity. Guinea-pigs were sensitised to Ova and challenged with inhaled Ova alone or combined with LPS. Airways function was determined by measuring specific airways conductance via whole-body plethysmography. Airways hyperresponsiveness to histamine was determined pre- and 24h post-Ova challenge. Airways inflammation and underlying mechanisms were determined from bronchoalveolar lavage cell counts and lung tissue cytokines. Vehicle or dexamethasone was administered by once-daily intraperitoneal injection (5, 10 or 20 mg/kg) or twice-daily inhalation (4 or 20 mg/ml) for 6 days before Ova challenge or Ova with LPS. LPS exacerbated Ova-induced responses, elongating early asthmatic responses (EAR), prolonging bronchoconstriction by histamine and further elevating airways inflammation. Intraperitoneal dexamethasone (20 mg/kg) significantly reduced the elongated EAR and airways inflammation but not the increased bronchoconstriction to histamine. In contrast, inhaled dexamethasone (20 mg/ml), which inhibited responses to Ova alone, did not significantly reduce functional and inflammatory responses to combined Ova and LPS. Combined Ova and LPS-induced functional and inflammatory responses are insensitive to inhaled but only partially sensitive to systemic dexamethasone. These results suggest that the route of corticosteroid administration may be important in determining the sensitivity of asthmatic responses to these agents.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Subjects: R Medicine > RS Pharmacy and materia medica
Uncontrolled Keywords: AHR, airways hyperresponsiveness; DMSO, dimethyl sulfoxide, EAR, early asthmatic response; FP, fluticasone propionate; GR, glucocorticoid receptor; LAR, late asthmatic response; LPS, lipopolysaccharide; Ova, ovalbumin; PI3K, phosphoinositide 3 kinase; sGaw, specific airway conductance; SEM, standard error of the mean
Publisher: American Society for Pharmacology and Experimental Therapeutics
ISSN: 0022-3565
Funders: MRC
Date of First Compliant Deposit: 27 June 2017
Date of Acceptance: 4 May 2017
Last Modified: 13 Apr 2019 02:15
URI: http://orca.cf.ac.uk/id/eprint/101778

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