Trefoil Factor–2 Reverses Airway Remodeling Changes in Allergic Airways Disease

Abstract

Trefoil factor 2 (TFF2) is a small peptide with an important role in mucosal repair. TFF2 is up-regulated in asthma, suggesting a role in asthma pathogenesis. Given its known biological role in promoting epithelial repair, TFF2 might be expected to exert a protective function in limiting the progression of airway remodeling in asthma. The contribution of TFF2 to airway remodeling in asthma was investigated by examining the expression of TFF2 in the airway and lung, and evaluating the effects of recombinant TFF2 treatment on established airway remodeling in a murine model of chronic allergic airways disease (AAD). BALB/c mice were sensitized and challenged with ovalbumin (OVA) or saline for 9 weeks, whereas mice with established OVA-induced AAD were treated with TFF2 or vehicle control (intranasally for 14 d). Effects on airway remodeling, airway inflammation, and airway hyperresponsiveness were then assessed, whereas TFF2 expression was determined by immunohistochemistry. TFF2 expression was significantly increased in the airways of mice with AAD, compared with expression levels in control mice. TFF2 treatment resulted in reduced epithelial thickening, subepithelial collagen deposition, goblet-cell metaplasia, bronchial epithelium apoptosis, and airway hyperresponsiveness (all P < 0.05, versus vehicle control), but TFF2 treatment did not influence airway inflammation. The increased expression of endogenous TFF2 in response to chronic allergic inflammation is insufficient to prevent the progression of airway inflammation and remodeling in a murine model of chronic AAD. However, exogenous TFF2 treatment is effective in reversing aspects of established airway remodeling. TFF2 has potential as a novel treatment for airway remodeling in asthma.

Characterization of a novel model incorporating airway epithelial damage and related fibrosis to the pathogenesis of asthma

“…Annexin V-associated apoptosis was also significantly higher in OVA-sensitized/ challenged mice compared to that measured in saline controls, 25 and was further increased in OVA þ NA-treated mice compared with OVA-sensitized/challenged animals, which was comparable to levels measured in NA alonetreated mice. As epithelial denudation was not observed in Figure 5 Determination of airway resistance from dose-response to methacholine.…”

“…Characterization of a novel model of asthma SG Royce et al repair peptide, trefoil factor 2, 23,25 it can be suggested that epithelial damage alone can lead to subepithelial airway fibrosis (as demonstrated by the increased NA-induced subepithelial collagen thickness and total lung collagen concentration), similar to processes occurring in human asthma where repeated episodes of epithelial injury lead to prolonged activation of the epithelial mesenchymal trophic unit. 26,27 Previous studies have shown that epithelial damage results in epithelial cells releasing pro-inflammatory factors such as IL-1 and tumor necrosis factor-a.…”

“…23,25 Despite its significance, epithelial damage has been poorly addressed in current experimental models used to study the pathogenesis of asthma, and also by currently available therapies for asthma. Thus, establishing experimental models of AAD that better reflect the pathogenesis of human asthma and incorporate the contribution of epithelial damage with other features of AWR and AHR is warranted.…”

“…The potential advantage of this combined OVA þ NA-treated model (over existing models) is that it incorporates AI, epithelial damage, AWR, and AHR as part of its pathology, and therefore is more likely to undergo structural and functional changes that are more reflective of human asthma. Additionally, given the striking increase in fibrosis and AHR that was observed in the combined model, perhaps this model can now be used to evaluate novel treatments that target epithelial damage (such as epithelial repair molecules and trefoil factors); 25 and related fibrosis (such as relaxin, 40 pirfenidone 41 and stem cells 42 ). The characterization of this model has led us to demonstrate that epithelial damage is a key contributor to airway fibrosis and related AHR, and exacerbates AIinduced AWR.…”

Parabromophenacyl Bromide Inhibits Subepithelial Fibrosis by Reducing TGF-β₁ in a Chronic Mouse Model of Allergic Asthma

“…Various reports have demonstrated the reversal of airway remodeling with a 14-day treatment protocol [13,14]. The major difference between our approach in this study and these published approaches was the continuation of the OVA challenge; in the previous reports, the challenge was stopped during treatment.…”