Soluble transforming growth factor-beta type III receptor gene transfection inhibits fibrous airway obliteration in a rat model of Bronchiolitis obliterans.
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-beta (TGFbeta) during the development of airway fibrous obliteration. Immunohistochemical analysis revealed TGFbeta staining in infiltrating mononuclear cells at Days 2 and 7, and in the fibrous tissues until Day 21. Soluble TGFbeta receptor type III (TGFBIIIR), by blocking TGFbeta binding to its membrane receptors, functions as a TGFbeta antagonist. To study the role of TGFbeta in the development of BO, adenoviral-mediated soluble TGFBIIIR gene transfection (5 x 10(9) 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 TGFbeta expressed in the allografts plays a pivotal role in the pathogenesis of BO. Soluble TGFBIIIR may competitively inhibit TGFbeta 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.
Liu
Mingyao
M
Thoracic Surgery Research Laboratory, University Health Network, Toronto General Hospital, Room 1-816, 200 Elizabeth Street, Toronto, Ontario, M5G 2C4 Canada. mingyao.liu@utoronto.ca
Suga
Michiharu
M
Maclean
Alexandra A
AA
St  George
Judith A
JA
Souza
David W
DW
Keshavjee
Shaf
S
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000150:complications*; D004195:Disease Models, Animal; D008297:Male; D011509:Proteoglycans / Q000096:biosynthesis / Q000235:genetics*; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000517:prevention & control*; D051381:Rats; D011914:Rats, Inbred BN; D011917:Rats, Inbred Lew; D018125:Receptors, Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D014162:Transfection
D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; C071736:betaglycan