title: Human parainfluenza type 3 virus impairs the efficacy of glucocorticoids to limit allergy-induced pulmonary inflammation in guinea-pigs.
abstract: Viral exacerbations of allergen-induced pulmonary inflammation in pre-clinical models reportedly reduce the efficacy of glucocorticoids to limit pulmonary inflammation and airways hyper-responsiveness to inhaled spasmogens. However, exacerbations of airway obstruction induced by allergen challenge have not yet been studied. hPIV-3 (human parainfluenza type 3 virus) inoculation of guinea-pigs increased inflammatory cell counts in BAL (bronchoalveolar lavage) fluid and caused hyper-responsiveness to inhaled histamine. Both responses were abolished by treatment with either dexamethasone (20 mg/kg of body weight, subcutaneous, once a day) or fluticasone propionate (a 0.5 mg/ml solution aerosolized and inhaled over 15 min, twice a day). In ovalbumin-sensitized guinea-pigs, allergen (ovalbumin) challenge caused two phases of airway obstruction [measured as changes in sGaw (specific airways conductance) using whole body plethysmography]: an immediate phase lasting between 4 and 6 h and a late phase at about 7 h. The late phase, airway hyper-responsiveness to histamine and inflammatory cell counts in BAL were all significantly reduced by either glucocorticoid. Inoculation of guinea-pigs sensitized to ovalbumin with hPIV-3 transformed the allergen-induced airway obstruction from two transient phases into a single sustained response lasting up to 12 h. This exacerbated airway obstruction and airway hyper-responsiveness to histamine were unaffected by treatment with either glucocorticoid whereas inflammatory cell counts in BAL were only partially inhibited. Virus- or allergen-induced pulmonary inflammation, individually, are glucocorticoid-sensitive, but in combination generate a phenotype where glucocorticoid efficacy is impaired. This suggests that during respiratory virus infection, glucocorticoids might be less effective in limiting pulmonary inflammation associated with asthma.
authors.affiliation: Cardiff School of Pharmacy and Pharmaceutical Sciences, School of Medicine, Cardiff University, Cardiff, UK. fordwr@cardiff.ac.uk
authors.forename: William R
authors.initials: WR
authors.lastname: Ford
authors.forename: Alan E
authors.initials: AE
authors.lastname: Blair
authors.forename: Rhys L
authors.initials: RL
authors.lastname: Evans
authors.forename: Elinor
authors.initials: E
authors.lastname: John
authors.forename: Joachim J
authors.initials: JJ
authors.lastname: Bugert
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Broadley
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Kidd
mesh_terms: D000280:Administration, Inhalation; D000485:Allergens / Q000276:immunology; D000730:Androstadienes / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000821:virology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D003907:Dexamethasone / Q000627:therapeutic use; D004351:Drug Resistance; D000068298:Fluticasone; D005938:Glucocorticoids / Q000008:administration & dosage / Q000627:therapeutic use*; D006168:Guinea Pigs; D006632:Histamine; D006801:Humans; D008297:Male; D010047:Ovalbumin / Q000276:immunology; D010224:Parainfluenza Virus 3, Human; D011014:Pneumonia / Q000188:drug therapy / Q000821:virology*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000821:virology*; D010253:Respirovirus Infections / Q000150:complications*
chemical_list: D000485:Allergens; D000730:Androstadienes; D005938:Glucocorticoids; D003907:Dexamethasone; D006632:Histamine; D010047:Ovalbumin; D000068298:Fluticasone