title: Intranasally administered serelaxin abrogates airway remodelling and attenuates airway hyperresponsiveness in allergic airways disease.
abstract: BACKGROUND
  The peptide hormone relaxin plays a key role in the systemic hemodynamic and renovascular adaptive changes that occur during pregnancy, which is linked to its antiremodelling effects. Serelaxin (a recombinant form of human gene-2 relaxin) has been shown to inhibit lung fibrosis in various disease models and reverse airway remodelling and airway hyperresponsiveness (AHR) in allergic airways disease (AAD).
  
  
  OBJECTIVE
  Although continuous systemic delivery of exogenous serelaxin alleviates allergic fibrosis and AHR, more direct routes for administration into the lung have not been investigated. Thus, intranasal administration of serelaxin was evaluated for its ability to reverse airway remodelling and AHR associated with AAD.
  
  
  METHODS
  Female Balb/c mice were subjected to a 9-week model of chronic AAD. Subgroups of animals (n = 12/group) were then treated intranasally with serelaxin (0.8 mg/mL) or vehicle once daily for 14 days (from weeks 9-11). Saline-sensitized/challenged mice treated with intranasal saline served as additional controls. Differential bronchoalveolar lavage (BAL) cell counts, ovalbumin (OVA)-specific IgE levels, tissue inflammation, parameters of airway remodelling and AHR were then assessed.
  
  
  RESULTS
  Chronic AAD was associated with significant increases in differential BAL cell counts, OVA-specific IgE levels, inflammation, epithelial thickening, goblet cell metaplasia, TGF-β1 expression, epithelial Smad2 phosphorylation (pSmad2), subepithelial collagen thickness, total lung collagen concentration and AHR (all P < 0.05 vs. respective measurements from saline-treated mice). Daily intranasal delivery of serelaxin significantly diminished AAD-induced epithelial thickening, epithelial pSmad2, subepithelial and total lung collagen content (fibrosis) and AHR (all P < 0.05 vs. vehicle-treated AAD mice).
  
  
  CONCLUSIONS
  Intranasal delivery of serelaxin can effectively reduce airway remodelling and AHR, when administered once daily. Respirable preparations of serelaxin may have therapeutic potential for the prevention and/or reversal of established airway remodelling and AHR in asthma.
authors.affiliation: Allergy and Immune Disorders, Murdoch Children's Research Institute, Melbourne, Vic., Australia; Department of Pharmacology, Monash University, Melbourne, Vic., Australia.
authors.forename: S G
authors.initials: SG
authors.lastname: Royce
authors.forename: C X F
authors.initials: CX
authors.lastname: Lim
authors.forename: K P
authors.initials: KP
authors.lastname: Patel
authors.forename: B
authors.initials: B
authors.lastname: Wang
authors.forename: C S
authors.initials: CS
authors.lastname: Samuel
authors.forename: M L K
authors.initials: ML
authors.lastname: Tang
mesh_terms: D000281:Administration, Intranasal; D056151:Airway Remodeling / Q000187:drug effects*; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D020397:Goblet Cells / Q000473:pathology; D007073:Immunoglobulin E / Q000276:immunology; D008168:Lung / Q000276:immunology / Q000473:pathology; D008679:Metaplasia; D051379:Mice; D010047:Ovalbumin / Q000009:adverse effects / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage*; D012065:Relaxin / Q000008:administration & dosage*; D012130:Respiratory Hypersensitivity / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology*; D020545:Respiratory Mucosa / Q000276:immunology / Q000473:pathology
chemical_list: D011994:Recombinant Proteins; D007073:Immunoglobulin E; D012065:Relaxin; D010047:Ovalbumin
keywords: airway hyperesponsiveness; airway remodelling; allergic airways disease; asthma; intranasal; serelaxin