Systemic overexpression of matricellular protein CCN1 exacerbates obliterative bronchiolitis in mouse tracheal allografts. (27th July 2015)

• Record Type: Journal Article
• Authors: Raissadati, Alireza; Nykänen, Antti I.; Tuuminen, Raimo; Syrjälä, Simo O.; Krebs, Rainer; Arnaudova, Ralica; Rouvinen, Eeva; Wang, Xiaomin; Poller, Wolfgang; Lemström, Karl B.
• Is Part Of: Transplant international. Volume 28:Number 12(2015:Dec.)
• Page Start: 1416
• Page End: 1425
• Publication Date: 2015-07-27
• Subjects: chronic lung allograft rejection -- cyclic arginine–glycine–aspartic acid peptide -- Cysteine‐rich 61 -- lung transplant obliterative bronciolitis -- mouse tracheal allograft; Transplantation of organs, tissues, etc -- Periodicals; 617.95405
• DOI: 10.1111/tri.12639
• Languages: English
• ISSNs: 0934-0874

Abstract

Summary: 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 αv β3 ‐integrin‐independent pathway. Further experiments are required to uncover its potentially harmful role in the development of OB after lung transplantation.