Systemic overexpression of matricellular protein CCN1 exacerbates obliterative bronchiolitis in mouse tracheal allografts |
| |
Authors: | Alireza Raissadati Antti I Nykänen Raimo Tuuminen Simo O Syrjälä Rainer Krebs Ralica Arnaudova Eeva Rouvinen Xiaomin Wang Wolfgang Poller Karl B Lemström |
| |
Institution: | 1. University of Helsinki/Transplantation Laboratory, and Helsinki University Central Hospital/Cardiac Surgery/Heart and Lung Center, Helsinki, Finland;2. Department of Cardiology and Pneumology, Charité – Universit?tsmedizin Berlin, Berlin, Germany;3. Berlin Center for Regenerative Therapies (BCRT), Charité – Universit?tsmedizin Berlin, Berlin, Germany |
| |
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. |
| |
Keywords: | chronic lung allograft rejection cyclic arginine– glycine– aspartic acid peptide Cysteine‐rich 61 lung transplant obliterative bronciolitis mouse tracheal allograft |
|
|