Combining an epithelial repair factor and anti‐fibrotic with a corticosteroid offers optimal treatment for allergic airways disease

• Published in: British journal of pharmacology Vol. 173; no. 12; pp. 2016 - 2029
• Main Authors: Patel, K P, Giraud, A S, Samuel, C S, Royce, S G
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01.06.2016; John Wiley and Sons Inc
• Subjects: Accumulation; Animals; Asthma; Asthma - complications; Asthma - drug therapy; Collagen; Corn oil; Corticoids; Corticosteroids; Dexamethasone; Dexamethasone - therapeutic use; Drug Therapy, Combination; Extracellular matrix; Female; Fibronectin; Fibrosis; Fibrosis - prevention & control; Hypersensitivity - complications; Hypersensitivity - drug therapy; Inflammation; Intranasal administration; Lungs; Medical treatment; Mice; Mice, Inbred BALB C; Naphthalene; Ovalbumin; Pathogenesis; Plethysmography; Research Paper; Research Papers; Respiratory function; Respiratory tract; Respiratory tract diseases; Rodents; Trefoil factor; Trefoil Factor-2 - drug effects
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/bph.13494

Background and Purpose We evaluated the extent to which individual versus combination treatments that specifically target airway epithelial damage [trefoil factor‐2 (TFF2)], airway fibrosis [serelaxin (RLX)] or airway inflammation [dexamethasone (DEX)] reversed the pathogenesis of chronic allergic airways disease (AAD). Experimental Approach Following induction of ovalbumin (OVA)‐induced chronic AAD in 6–8 week female Balb/c mice, animals were i.p. administered naphthalene (NA) on day 64 to induce epithelial damage, then received daily intranasal administration of RLX (0.8 mg·mL−1), TFF2 (0.5 mg·mL−1), DEX (0.5 mg·mL−1), RLX + TFF2 or RLX + TFF2 + DEX from days 67–74. On day 75, lung function was assessed by invasive plethysmography, before lung tissue was isolated for analyses of various measures. The control group was treated with saline + corn oil (vehicle for NA). Key Results OVA + NA‐injured mice demonstrated significantly increased airway inflammation, airway remodelling (AWR) (epithelial damage/thickness; subepithelial myofibroblast differentiation, extracellular matrix accumulation and fibronectin deposition; total lung collagen concentration), and significantly reduced airway dynamic compliance (cDyn). RLX + TFF2 markedly reversed several measures of OVA + NA‐induced AWR and normalized the reduction in cDyn. The combined effects of RLX + TFF2 + DEX significantly reversed peribronchial inflammation score, airway epithelial damage, subepithelial extracellular matrix accumulation/fibronectin deposition and total lung collagen concentration (by 50–90%) and also normalized the reduction of cDyn. Conclusions and Implications Combining an epithelial repair factor and anti‐fibrotic provides an effective means of treating the AWR and dysfunction associated with AAD/asthma and may act as an effective adjunct therapy to anti‐inflammatory corticosteroids.