title: Systemic overexpression of matricellular protein CCN1 exacerbates obliterative bronchiolitis in mouse tracheal allografts.
abstract: Obliterative bronchiolitis (OB) involves airway epithelial detachment, fibroproliferation, and inflammation, resulting in chronic rejection and transplant failure. Cysteine-rich 61 (CCN1) is an integrin receptor antagonist with a context-dependent role in inflammatory and fibroproliferative processes. We used a mouse tracheal OB model to investigate the role of CCN1 in the development of lung allograft OB. C57Bl/6 mice received a systemic injection of CCN1-expressing adenoviral vectors 2 days prior to subcutaneous implantation of tracheal allografts from major MHC-mismatched BALB/c mice. We treated another group of tracheal allograft recipients with cyclic arginine-glycine-aspartic acid peptide to dissect the role of αvβ3-integrin signaling in mediating CCN1 effects in tracheal allografts. Allografts were removed 4 weeks after transplantation and analyzed for luminal occlusion, inflammation, and vasculogenesis. CCN1 overexpression induced luminal occlusion (P < 0.05), fibroproliferation, and smooth muscle cell proliferation (P < 0.05). Selective activation of αvβ3-integrin receptor failed to mimic the actions of CCN1, and blocking failed to inhibit the effects of CCN1 in tracheal allografts. In conclusion, CCN1 exacerbates tracheal OB by enhancing fibroproliferation via an αvβ3-integrin-independent pathway. Further experiments are required to uncover its potentially harmful role in the development of OB after lung transplantation.
authors.affiliation: University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center, Helsinki, Finland.
authors.forename: Alireza
authors.initials: A
authors.lastname: Raissadati
authors.affiliation: University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center, Helsinki, Finland.
authors.forename: Antti I
authors.initials: AI
authors.lastname: Nykänen
authors.affiliation: University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center, Helsinki, Finland.
authors.forename: Raimo
authors.initials: R
authors.lastname: Tuuminen
authors.affiliation: University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center, Helsinki, Finland.
authors.forename: Simo O
authors.initials: SO
authors.lastname: Syrjälä
authors.affiliation: University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center, Helsinki, Finland.
authors.forename: Rainer
authors.initials: R
authors.lastname: Krebs
authors.affiliation: University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center, Helsinki, Finland.
authors.forename: Ralica
authors.initials: R
authors.lastname: Arnaudova
authors.affiliation: University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center, Helsinki, Finland.
authors.forename: Eeva
authors.initials: E
authors.lastname: Rouvinen
authors.affiliation: Department of Cardiology and Pneumology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology and Pneumology, Charité - Universitätsmedizin Berlin, Berlin, Germany.|Berlin Center for Regenerative Therapies (BCRT), Charité - Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Poller
authors.affiliation: University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center, Helsinki, Finland.
authors.forename: Karl B
authors.initials: KB
authors.lastname: Lemström
mesh_terms: D064591:Allografts; D000818:Animals; D001989:Bronchiolitis Obliterans / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition; D006084:Graft Rejection / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D039302:Integrin alphaVbeta3 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D032389:Myocytes, Smooth Muscle / Q000378:metabolism / Q000473:pathology; D010456:Peptides, Cyclic / Q000008:administration & dosage; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014132:Trachea / Q000637:transplantation*; D015854:Up-Regulation
chemical_list: C491850:CCN1 protein, mouse; D055515:Cysteine-Rich Protein 61; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; D011994:Recombinant Proteins; C507169:cyclic arginine-glycine-aspartic acid peptide
keywords: Cysteine-rich 61; chronic lung allograft rejection; cyclic arginine-glycine-aspartic acid peptide; lung transplant obliterative bronciolitis; mouse tracheal allograft