Background/Purpose: Pulmonary fibrosis (PF) is the leading cause of death in systemic sclerosis.  Pathologically, PF is characterized by an aberrant wound healing repair mechanism leading to excessive fibroblast proliferation, myofibroblast differentiation, and extensive matrix deposition in the alveolar airways. Epithelial-to-mesenchymal transition (EMT) is the differentiation of fibroblast-like phenotype from epithelial cells that results in myofibroblast accumulation. Cadherin-11 (Cad11), a mesenchymal, homophillic adhesion molecule, has been reported to be expressed on hyperplastic alveolar epithelial cells (AEC), a populations of cells postulated to be undergoing EMT during the development of fibrosis.  However it is not known if Cad11 is a regulator of EMT and if this contributes to the development of PF. We hypothesized that Cad11 contributes to the development of pulmonary fibrosis through the regulation of EMT.

Methods: Cad11 deficient mice and neutralizing Cad11 monoclonal antibodies were used to determine the role of Cad11 in the intraperitoneal (IP) bleomycin (BLM) model of pulmonary fibrosis that exhibits EMT.  AEC cell lines (A549, MLE-12) and primary murine AEC induced to undergo EMT by TGF-beta were used to determine if Cad11 regulates EMT in vitro.

Results: Cad11 deficient mice had reduced fibrosis in the IP BLM model as assessed by improved arterial oxygen saturation, decreased collagen deposition, diminished alpha-smooth muscle actin (aSMA) accumulation, decreased TGF-b production and reduced b-catenin expression.  These findings were confirmed using neutralizing antiCad11 monoclonal antibodies in wild type mice. In vitrostudies demonstrated that activation of Cad11 using immobilized Cad11-Fc fusion protein increased Col1a expression by A549 and MLE-12 AEC. In contrast, siRNA knockdown of Cad11 expression in A549 and MLE-12 AEC decreased the expression of fibrotic genes such as Col1a, aSMA, and CTGF.  In addition, primary AECs from Cad11 deficient mice had decreased capacity to undergo EMT induced by TGF-beta relative to primary AECs from wild type mice. Finally, Cad11 inhibition with soluble Cad11-Fc fusion protein reduced EMT markers in wild type AECs treated with TGF-beta.

Conclusion: These findings demonstrate that Cad11 is an important mediator of EMT in vitro and pulmonary fibrosis in vivo.  Furthermore, these data suggest that Cad11 may be a therapeutic target in the treatment of pulmonary fibrosis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cadherin-11-regulates-pulmonary-fibrosis-in-bleomycin-induced-lung-injury/