Transient transgene expression of decorin in the lung reduces the fibroticresponse to bleomycin

Pulmonary fibrosis is a chronic progressive disease with no effective thera py. Transforming growth factor beta (TGF-beta) is thought to be a key profi brotic mediator and blocking its activity is therefore one of the targets o f new treatment strategies for fibrosis. Decorin is an endogenous proteogly can and one of the known inhibitors of TGF-beta. The short half-life of pep tide-based therapeutics makes gene transfer a promising approach to achieve prolonged protein levels in the lung. Replication-deficient adenovirus was used to deliver decorin transgene (AdDec) to the airways by a single intra nasal injection in a murine bleomycin model of lung fibrosis. The ability o f vector-derived decorin to inhibit TCF-beta was examined in a bioassay and its effect on bleomycin-induced pulmonary fibrosis was determined by histo morphology and lung hydroxyproline. In vitro, supernatant from cells infect ed with AdDec abrogated the bioactivity of TGF-beta in a dose-dependent man ner whereas control virus (AdDL70) had no effect. In vivo, treatment of ble omycin-injected mice with AdDec substantially reduced the fibrogenic respon se compared with control virus (hydroxyproline: bleomycin/AdDec, 1.96 mug/m g; bleomycin/AdDL70, 3.05 mug/mg; p = 0.0005). These results suggest that a single administration of AdDec was able to generate a local pulmonary envi ronment that effectively blocked the fibrogenic response to bleomycin by in hibition of TCF-beta.