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Towards an Effective Gene Therapy for Idiopathic Pulmonary Fibrosis*: Anti-inflammation, Antifibrosis, and Regeneration

Masahito Ebina, MD, PhD; M. Shimizukawa, MD; K. Narumi, MD; M. Miki, MD; D. Koinuma, MD; M. Watanabe, MD; H. Munakata, MD; T. Nukiwa, MD
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*From Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, (Drs. Ebina, Shimizukawa, Narumi, Miki, Koinuma, Watanabe, and Nukiwa), Tohoku University, Sendai; and Second Department of Biochemistry (Dr. Munakata), Kinki University School of Medicine, Kinki, Japan.

Correspondence to: Masahito Ebina, MD, PhD, Section Head, Molecular Pathology and Immunology, Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, 4–1, Seiryo, Aoba-Ku, Sendai, Japan; e-mail: ebinam@idac.tohoku.ac.jp



Chest. 2002;121(3_suppl):32S-33S. doi:10.1378/chest.121.3_suppl.32S-a
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An effective gene therapy is required for idiopathic pulmonary fibrosis (IPF) because (1) IPF is a chronic but progressive lung disease for which current therapy is minimally effective, (2) the molecular mechanism of complicated pathogenesis of IPF has been intensely studied and the candidate genes playing the key roles have been revealed, and (3) single gene delivery or single gene knockout has been reported to be effective for reducing fibrosis in the lungs of an experimental IPF model. We have examined the effect of lung regeneration by gene delivery of hepatocyte growth factor to bleomycin-induced fibrosis of mouse lung. We also revealed antifibrotic effect of decorin, a small leucine-rich proteoglycan, known as an intrinsic negative regulator of transforming growth factor-β, a key inducer of pulmonary fibrosis, using an adenoviral vector expressing human decorin, driven by cytomegalovirus promotor (AdCMV.DC). With intratracheal administration of AdCMV.DC to C57BL/6 mice with bleomycin-induced lung injury, the relative content of hydroxyproline was reduced but lung inflammation was prolonged. No reduction of hydroxyproline content by IV administration of AdCMV.DC suggested that adenoviral-mediated decorin treatment is effective only by direct administration to the injured lung, a finding which is different from the results of hepatocyte growth factor. We overviewed our gene delivery trials to pulmonary fibrosis, from the points of anti-inflammation, antifibrosis, and regeneration.

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