Combining an epithelial repair factor and anti-fibrotic with a corticosteroid offers optimal treatment for the pathogenesis of allergic airways disease

Abstract

The extent to which individual vs combination treatments that specifically targeted epithelial damage (trefoil factor-2, TFF2), fibrosis (serelaxin, RLX) or inflammation (AI; dexamethasone, DEX) reversed the pathogenesis of chronic allergic airways disease (AAD) was assessed. Following induction of a 9-week ovalbumin (OVA)-induced model of chronic AAD in 6-8week old female Balb/c mice, animals were i.p-administered with naphthalene (NA); then received daily i.n-administration of saline (vehicle); RLX (0.8mg/ml); TFF2 (0.5mg/ml); DEX (0.5mg/ml); RLX+TFF2; or RLX+TFF2+DEX from d67-74. On d75, lung function was assessed by plethysmography, beforelung tissue was taken for analysis. A control group treated with saline+corn oil (Saline/CO; vehicle for NA) was included. A significant increase in AI, epithelial damage/thickness; myofibroblast differentiation; subepithelial/total collagen and fibronectin deposition; and a significant reduction in airway dynamic compliance (cDyn) was observed in OVA+NA injured mice (all p<0.01 vs Saline/CO group). RLX+TFF2 markedly reversed several measures of OVA+NA induced AWR and normalized the reduction of cDyn (all p<0.05 vs OVA+NA group). The combined effects of RLN, TFF2 and DEX maximally reversed peribronchial inflammation score, airway epithelial damage, subepithelial/total lung collagen deposition and subepithelial fibronectin deposition (∼50-90%); and normalized the OVA+NA-induced impairment of cDyn (all p<0.05 vs OVA+NA group). Thus, combining an epithelial repair factor and anti-fibrotic with a corticosteroid offers optimal treatment against the pathogenesis of chronic AAD/asthma.