Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice
Atsuhito Nakao, … , Kohei Miyazono, Itsuo Iwamoto
Atsuhito Nakao, … , Kohei Miyazono, Itsuo Iwamoto
Published July 1, 1999
Citation Information: J Clin Invest. 1999;104(1):5-11. https://doi.org/10.1172/JCI6094.
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Article

Transient gene transfer and expression of Smad7 prevents bleomycin-induced lung fibrosis in mice

Abstract

TGF-β plays an important role in lung fibrosis, which is a major cause of suffering and death seen in pulmonary disease. Smad7 has been recently identified as an antagonist of TGF-β signaling. To investigate whether this novel molecule can be exploited for therapy of lung fibrosis, we determined the effect of exogenous Smad7, introduced by a recombinant human type 5 adenovirus vector, on bleomycin-induced lung fibrosis in mice. C57BL/6 mice with bleomycin-induced lungs received an intratracheal injection of a recombinant adenovirus carrying mice Smad7 cDNA. These mice demonstrated suppression of type I precollagen mRNA, reduced hydroxyproline content, and no morphological fibrotic responses in the lungs when compared with mice administered adenovirus carrying Smad6 cDNA. In addition, we found that expression of Smad7 transgene blocked Smad2 phosphorylation induced by bleomycin in mouse lungs. These data indicated that gene transfer of Smad7 (but not Smad6) prevented bleomycin-induced lung fibrosis, suggesting that Smad7 may have applicability in the treatment of pulmonary fibrosis.

Authors

Atsuhito Nakao, Makiko Fujii, Ryutaro Matsumura, Kotaro Kumano, Yasushi Saito, Kohei Miyazono, Itsuo Iwamoto

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Effect of exogenous Smad7 on bleomycin-induced lung fibrosis in mice. (a...
Effect of exogenous Smad7 on bleomycin-induced lung fibrosis in mice. (a) Lung fibrosis was induced by continuous subcutaneous infusion of bleomycin (100 mg/kg for 7 days) from days 0–7 in C57BL/6 mice. Mice were infected with recombinant adenovirus (AdCMV-Smad6 or AdCMV-Smad7) by intratracheal injection with 109 pfu/mouse at day 0. Mice were sacrificed after 4 weeks, and the lungs were fixed in 10% formalin and stained with hematoxylin/eosin/safranin O. Left: treatment with bleomycin plus AdCMV-Smad6. Note the thickened continuous interalveolar septa. Right: treatment with bleomycin plus AdCMV-Smad7. Note the absence of thickened interalveolar septa, although some increased cellularity in interalveolar septa was observed. (b) Scoring of lung fibrosis. Fibrotic changes in mouse lung (S0–S3 = score 0–3, respectively) were graded according to the criteria described in Methods.