Intratracheal gene transfer of decorin reduces subpleural fibroproliferation induced by bleomycin.
Decorin, a small leucin-rich proteoglycan, is a negative regulator of transforming growth factor-beta, but the antifibrotic effect of decorin gene transfer has not been examined in a mouse model of usual interstitial pneumonia (UIP). We constructed a replication-defective recombinant adenovirus harboring human decorin gene (AdCMV.DC) and administered 1 x l0(9) plaque-forming units of AdCMV.DC intratracheally or intravenously to C57BL/6 mice with intraperitoneal injection of bleomycin, which induces a subpleural fibroproliferation, mimicking UIP, by day 28. Only intratracheal administration of AdCMV.DC increased decorin mRNA expression in the lung and decreased the hydroxyproline content augmented in bleomycin-induced pulmonary fibrosis (1.13 +/- 0.02 to 0.96 +/- 0.02, P = 0.006). In contrast, intravenous administration of AdCMV.DC increased the decorin expression only in the liver, but not in the lung, and without reducing lung fibrosis. These results indicate that adenoviral decorin gene transfer is effective only by direct administration to fibrosing lungs.
Shimizukawa
Minoru
M
Department of Respiratory Oncology and Molecular Medicine, Institute of Development, Aging, and Cancer, Tohoku University, Sendai 980-8575, Japan.
Ebina
Masahito
M
Narumi
Ko
K
Kikuchi
Toshiaki
T
Munakata
Hiroshi
H
Nukiwa
Toshihiro
T
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000964:Antimetabolites, Antineoplastic; D001761:Bleomycin; D002460:Cell Line; D058575:Decorin; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins; D005260:Female; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006801:Humans; D007275:Injections, Intravenous; D007322:Instillation, Drug; D008099:Liver / Q000378:metabolism; D008168:Lung / Q000378:metabolism; D017563:Lung Diseases, Interstitial / Q000139:chemically induced / Q000473:pathology / Q000628:therapy; D051379:Mice; D008907:Mink; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D012333:RNA, Messenger / Q000096:biosynthesis; D014132:Trachea / Q000378:metabolism; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors
D000964:Antimetabolites, Antineoplastic; C546878:DCN protein, human; C546879:Dcn protein, mouse; D058575:Decorin; D016326:Extracellular Matrix Proteins; D011509:Proteoglycans; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D001761:Bleomycin