Am. J. Respir. Crit. Care Med., Volume 165, Number 3, February 2002, 419-423

Soluble Transforming Growth Factor- Type III Receptor Gene Transfection Inhibits Fibrous Airway Obliteration in a Rat Model of Bronchiolitis Obliterans

MINGYAO LIU, MICHIHARU SUGA, ALEXANDRA A. MACLEAN, JUDITH A. ST. GEORGE, DAVID W. SOUZA, and SHAF KESHAVJEE

Thoracic Surgery Research Laboratory, University Health Network Toronto General Research Institute and Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Genzyme Corporation, Framingham, Massachusetts

Post-transplant bronchiolitis obliterans (BO) is characterized by fibroproliferation and fibrous obliteration of distal airways in chronically rejected lungs. In this study, using a rat heterotopic allogeneic tracheal transplant model of BO, we evaluated the expression of transforming growth factor- (TGF) during the development of airway fibrous obliteration. Immunohistochemical analysis revealed TGF staining in infiltrating mononuclear cells at Days 2 and 7, and in the fibrous tissues until Day 21. Soluble TGF receptor type III (TGFBIIIR), by blocking TGF binding to its membrane receptors, functions as a TGF antagonist. To study the role of TGF in the development of BO, adenoviral-mediated soluble TGFBIIIR gene transfection (5 × 10⁹ particles) was performed topically at the site of transplant on Day 5 after transplantation, which leads to inhibition of fibrous airway obliteration. In contrast, empty vector gene delivered through intramuscular injection, or given locally at Days 0 or 10 after tracheal transplantation had no significant effect. These results suggest that TGF expressed in the allografts play a pivotal role in the pathogenesis of BO. Soluble TGFBIIIR may competitively inhibit TGF activity locally. Adenoviral-mediated soluble TGFBIIIR gene transfection should be further explored as a potential therapeutic modality for BO and other conditions involving chronic fibrosis.

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