ORIGINAL ARTICLE

Receptor-activated Smad localisation in Bleomycin-induced pulmonary fibrosis

Hiroyuki Higashiyama, Daisuke Yoshimoto, Yuji Okamoto, Hideo Kikkawa, Satoshi Asano and Mine Kinoshita

Department of Pharmacology, Tsukuba Research Laboratories, GlaxoSmithKline, Tsukuba, Ibaraki, Japan

Correspondence to:
Correspondence to:
Dr S Asano
Department of Pharmacology, Tsukuba Research Laboratories, GlaxoSmithKline, 43 Wadai, Tsukuba, Ibaraki 300-4247, Japan;satoshi.asano{at}gsk.com

Background: Recent advances in fibrosis biology have identified transforming growth factor (TGF)-ß type I receptor-mediated activation of Smads as playing a central part in the development of fibrosis. However, to date, there have been few studies that examined the localisation and distribution of receptor-activated Smads protein (R-Smads: Smad2 and 3) during the fibrosis progression.

Aims: To histopathologically assess the time-course change of the localisation and distribution of the Smads protein in pulmonary fibrosis.

Methods: Pulmonary fibrosis was induced by intranasal injection of bleomycin (0.3 U/mouse). Lungs were isolated 2, 5, 7, 9 and 14 days after bleomycin treatment. Histological changes in the lungs were evaluated by haematoxylin-eosin stain or Masson’s trichrome stain, and scored. TGF-ß1, Smad3 and phosphorylated Smad2 localisations in lung tissues were determined by immunohistochemistry.

Results: The bleomycin treatment led to considerable pulmonary fibrotic changes accompanied by marked increase in TGF-ß1 expression in infiltrating macrophages. With the progression in fibrosis (day 7–14), marked increases in Smad3-positive and pSmad2-positive cells were observed. There were intense Smad3-positive and pSmad2-positive signals localised to the nuclei of the infiltrating macrophages and to type II epithelial cells, and less intense signals in fibroblasts and hyperplastic alveolar/bronchiolar epithelial cells.

Conclusions: The time-course data of TGF-ß1 and R-Smads indicate that progressive enhancement of TGF-ß1 signalling via R-Smad is activated in the process of fibrosis progression.

Abbreviations: ECM, extracellular matrix; TGF, transforming growth factor

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