Route of Administration Affects Corticosteroid Sensitivity of a Combined Ovalbumin and Lipopolysaccharide Model of Asthma Exacerbation in Guinea Pigs.

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. This study aimed 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 sensitivity. Guinea pigs were sensitized to Ova and challenged with inhaled Ova alone or combined with LPS. Airway function was determined by measuring specific airway conductance via whole-body plethysmography. Airway hyper-responsiveness to histamine was determined before and 24 hours post-Ova challenge. Airway inflammation and underlying mechanisms were determined from bronchoalveolar lavage cell counts and lung tissue cytokines. Vehicle or dexamethasone was administered by once-daily i.p. 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 histamine bronchoconstriction, and further elevating airway inflammation. Intraperitoneal dexamethasone (20 mg/kg) significantly reduced the elongated EAR and airway 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 they are only partially sensitive to systemic, dexamethasone. This finding suggests that the route of corticosteroid administration may be important in determining corticosteroid sensitivity of asthmatic responses.

• Authors: Alexander P P Lowe, Rhian S Thomas, Anthony T Nials, Emma J Kidd, Kenneth J Broadley, William R Ford
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 362 Issue 2 Pg. 327-337 (08 2017) ISSN: 1521-0103 [Electronic] United States
• PMID: 28576975 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 by The Author(s).

Chemical References

• Adrenal Cortex Hormones
• Drug Combinations
• Lipopolysaccharides
• Ovalbumin

Topics

• Administration, Inhalation
• Adrenal Cortex Hormones (administration & dosage)
• Animals
• Asthma (chemically induced, drug therapy, metabolism)
• Bronchial Hyperreactivity (chemically induced, drug therapy, metabolism)
• Drug Administration Routes
• Drug Combinations
• Guinea Pigs
• Injections, Intraperitoneal
• Lipopolysaccharides (administration & dosage, toxicity)
• Male
• Ovalbumin (administration & dosage, toxicity)
• Respiratory Hypersensitivity (chemically induced, drug therapy, metabolism)