Abstract
<h3>Purpose</h3> Multiple immunologic and physiologic insults can contribute to chronic lung allograft dysfunction (CLAD). Thy-1 is a surface glycoprotein that can downregulate fibroblast differentiation to myofibroblasts and fibroblast activation. The role of Thy-1 in CLAD has not been explored. <h3>Methods</h3> We utilized the minor antigen mismatched C57BL/6 (B6)→C57BL/10 (B10) model of murine lung transplantation. To mimic bacterial infection some mice received LPS (5μg in 50μl PBS/dose) intratracheally every 4 days until sacrifice on postoperative day 30 while some mice were treated with saline. We transplanted either wild type B6 or Thy-1 deficient grafts to B10 recipient mice (B6<sup>wt</sup>→B10 vs. B6<sup>Thy1-/−</sup>→B10). Grafts were assessed based on histological grading for obliterative bronchiolitis (OB) and parenchymal fibrosis. To assess the role of LPS on fibroblast-specific Thy-1 expression, we utilized primary cell cultures of murine lung fibroblasts isolated from B6 mice, using media containing 1μg/ml of LPS. <h3>Results</h3> LPS treatment resulted in CLAD which was more severe in B6<sup>Thy1-/-</sup> donors(Figure A).More importantly immunohistochemical evaluation demonstrated that that all OB and fibrotic lesion, even in wild-type donors consisted of Thy-1 negative fibroblast. In vitro administration of LPS significantly downregulated Thy-1 in wild-type fibroblast through the downregulation of protein-specific mRNA (<i>P</i><0.05) (Figure B). <h3>Conclusion</h3> We for the first time demonstrate the link between the downregulation of Thy-1 and CLAD. We also demonstrate that LPS results in loss of Thy-1 on stromal cells thus contributing to proliferative airway lesions and parenchymal fibrosis. Our findings suggest that Thy-1 replacement may serve as a therapeutic option to prevent chronic rejection.
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