Mediators of airway remodelling in asthma

Abstract

The asthmatic airway demonstrates structural changes termed airway remodelling which include subepithelial collagen deposition and an increase in numbers of myofibroblasts in the mucosa. These changes may contribute to bronchial hyperresponsiveness and to decline in lung function in asthma.

The hypothesis was proposed that proteases, and in particular the plasminogen activating system, may mediate airway remodelling through the release of growth factors such as basic fibroblast growth factor (bFGF) and transforming growth factor-beta (TGF-β) from their binding to the extracellular matrix. The ability of bronchoalveolar lavage fluid (BALF) from asthmatic and non asthmatic subjects to stimulate proliferation in vitro of a transformed human fetal lung fibroblast cell line, MRC-5, was studied by measuring ³H-thymidine uptake.

Use of blocking antibodies and antiproteases demonstrated significant inhibition of BALF-induced fibroblast DNA synthesis (BIDS) by anti-bFGF, by a protease inhibitor cocktail and by the specific plasmin inhibitor, α2-antiplasmin. Plasmin concentrations of BALF correlated with BIDS. Plasmin was shown to stimulate marked proliferation of fibroblasts, an effect that was profoundly inhibited by anti-bFGF. Measurement of cell supernatant concentrations demonstrated rapid release of bFGF from fibroblasts exposed to plasmin. Immunofluorescent confocal microscopy demonstrated plasmin-induced loss of bFGF staining from fibroblasts in vitro. These observations suggest that plasmin is an important fibroproliferative agent in BALF mediating its activity through autocrine release of bFGF.

BIDS within an asthmatic group correlated significantly with bronchial hyperresponsiveness and BALF from steroid-naïve asthmatic subjects with marked bronchial hyperresponsiveness stimulated significantly greater BIDS than that from non-asthmatic subjects. BIDS also correlated with plasmin, bFGF and TGF-β levels in the BALF. Six weeks treatment with inhaled budesonide, nedocromil or placebo led to significant reductions in BIDS and plasmin concentrations only in the inhaled corticosteroid group and bFGF concentrations fell following treatment with budesonide, a change that was significantly different from that due to placebo.

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