title: Regression of allograft airway fibrosis: the role of MMP-dependent tissue remodeling in obliterative bronchiolitis after lung transplantation.
abstract: Obliterative bronchiolitis after lung transplantation is a chronic inflammatory and fibrotic condition of small airways. The fibrosis associated with obliterative bronchiolitis might be reversible. Matrix metalloproteinases (MMPs) participate in inflammation and tissue remodeling. MMP-2 localized to myofibroblasts in post-transplant human obliterative bronchiolitis lesions and to allograft fibrosis in a rat intrapulmonary tracheal transplant model. Small numbers of infiltrating T cells were also observed within the fibrosis. To modulate inflammation and tissue remodeling, the broad-spectrum MMP inhibitor SC080 was administered after the allograft was obliterated, starting at post-transplant day 21. The allograft lumen remained obliterated after treatment. Only low-dose (2.5 mg/kg per day) SC080 significantly reduced collagen deposition, reduced the number of myofibroblasts and the infiltration of T cells in association with increased collagenolytic activity, increased MMP-2 gene expression, and decreased MMP-8, MMP-9, and MMP-13 gene expression. In in vitro experiments using cultured myofibroblasts, a relatively low concentration of SC080 increased MMP-2 activity and degradation of type I collagen. Moreover, coculture with T cells facilitated persistence of myofibroblasts, suggesting a role for T-cell infiltration in myofibroblast persistence in fibrosis. By combining low-dose SC080 with cyclosporine in vivo at post-transplant day 28, partial reversal of obliterative fibrosis was observed at day 42. Thus, modulating MMP activity might reverse established allograft airway fibrosis by regulating inflammation and tissue remodeling.
authors.affiliation: Latner Thoracic Surgery Research Laboratories, Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sato
authors.forename: David M
authors.initials: DM
authors.lastname: Hwang
authors.forename: Zehong
authors.initials: Z
authors.lastname: Guan
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Yeung
authors.forename: Masaki
authors.initials: M
authors.lastname: Anraku
authors.forename: Dirk
authors.initials: D
authors.lastname: Wagnetz
authors.forename: Shin
authors.initials: S
authors.lastname: Hirayama
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Waddell
authors.forename: Mingyao
authors.initials: M
authors.lastname: Liu
authors.forename: Shaf
authors.initials: S
authors.lastname: Keshavjee
mesh_terms: D000328:Adult; D056151:Airway Remodeling / Q000187:drug effects; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000201:enzymology* / Q000473:pathology / Q000517:prevention & control; D016572:Cyclosporine / Q000008:administration & dosage; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D005355:Fibrosis; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage; D008168:Lung / Q000473:pathology; D016040:Lung Transplantation; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000008:administration & dosage / Q000378:metabolism* / Q000502:physiology; D058628:Myofibroblasts / Q000187:drug effects; D011183:Postoperative Complications / Q000201:enzymology* / Q000517:prevention & control; D051381:Rats; D014184:Transplantation, Homologous
chemical_list: D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D061965:Matrix Metalloproteinase Inhibitors; D016572:Cyclosporine; D020782:Matrix Metalloproteinases