Attenuation of pulmonary fibrosis in type I collagen-targeted reporter mice with ALK-5 inhibitors

Publication date: Available online 15 November 2018Source: Pulmonary Pharmacology & TherapeuticsAuthor(s): Hideki Terashima, Misato Aonuma, Hiroshi Tsuchida, Kotaro Sugimoto, Mika Yokoyama, Mikio KatoAbstractIdiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease, and consequently, effective antifibrotic drugs are strongly desired. Although we have previously reported a validated Col1a1-Luc Tg rat model for fibrosis, there are only a few mouse models that enable the evaluation of fibrosis in a short time period and with high sensitivity. Therefore, we generated a Col1a1-internal ribosome entry site (IRES)-Luc knock-in (KI) mouse in which the IRES-luciferase gene construct was inserted into the 3′-UTR of the type I collagen alpha 1 gene (Col1a1). There was a high correlation between luciferase activity and hydroxyproline content in the KI mice, which is similar to the result that we have previously reported for the Col1a1-Luc Tg rat model. In a bleomycin (BLM)-induced lung fibrosis model, luciferase activity in the lung showed a significant increase 3 days after BLM treatment, while only a slight increase was observed in the hydroxyproline content. An ALK-5 inhibitor—R-268712—was effective in inhibiting the luciferase activity in both the in vivo BLM-induced lung fibrosis model and in vitro primary mouse lung fibroblasts. This suggests that fibroblasts are the major collagen-producing cells in lung fibrosis. In human lung fibroblasts, TGF-β stimulation in...
Source: Pulmonary Pharmacology and Therapeutics - Category: Respiratory Medicine Source Type: research