Potential role of KDAF in regulation of airway remodeling in asthma

Abstract

Rationale Subepithelial fibrosis is a major feature of airway remodeling in asthma characterized by increased deposition of collagen and decreased ability of fibroblasts to produce collagenase. Our group has recently identified a family of proteins, keratinocyte anti-fibrogenic factor (KDAF) that induce collagenase expression in dermal fibroblasts. We examined the ability of lung epithelial cells to release KDAF and assessed its effect on collagenase production from fibroblasts, in vitro. We also studied antifibrotic effects of KDAF in the presence of transforming growth factor-β 1(TGF-β 1), a known contributor to the development of peribronchiolar fibrosis in asthma. Methods A549 and HS24 cell lines were incubated with low FBS concentration medium for 24 h. The epithelial conditioned medium (CM) was subjected to Western blot analysis to detect KDAF. MMP-1 and type I collagen mRNA expression was examined by Northern blot analysis following treatment (24 hr) with CM and recombinant KDAF (2.5μg/ml). The effect of TGF-β 1(150 pg/ml) on production of MMP-1 was examined in the presence and absence of recombinant KDAF (2.5 μg/ml) and CM. Results A549 and HS24 epithelial cells released measurable KDAF the latter increased MMP-1 expression and decreased type I collagen production in fetal fibroblasts. Upregulation of MMP-1 expression in fibroblasts was sustained following treatment with TGF-β 1 in the presence of CM and recombinant KDAF. Conclusions Lung epithelial cell-derived KDAF appears to have potent antifibrotic effects. We postulate that reduction of KDAF in asthmatic airways may contribute to the development of profibrotic events leading to airway remodeling.