Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Cadherin 11 Promotes Pulmonary Fibrosis through Production of TGF and the Regulation of Epithelial to Mesenchymal Transition.
Schneider1, Daniel J., Wu4, Minghua, Le2, Thuy T., Cho3, Seo-Hee, Brenner5, Michael B., Blackburn2, Michael R., Agarwal4, Sandeep K.
Department of Biochemistry and Molecular Biology, University of Texas Health Science Center, Houston, TX
Department of Biochemistry and Molecular Biology, University of Texas Health Science Center
Department of Pediatrics, Pediatric Research Center, University of Texas Health Science Center
Division of Rheumatology and Clinical Immunogenetics, The University of Texas-Houston Medical School, Houston, TX
Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School
A devastating component of autoimmune disorders including systemic sclerosis is pulmonary fibrosis (PF). PF is characterized by excess deposition of extracellular matrix by myofibroblasts. Epithelial to mesenchymal transition (EMT) is a potential source of myofibroblasts. Cadherin 11 (CDH11) may contribute to processes that parallel those seen in PF and EMT, thus we hypothesized that CDH11 is a key mediator of PF.
CDH11 expression was determined in lung tissue from idiopathic pulmonary fibrosis (IPF) patients with severe (n=10) and mild (n=10) airway restriction and in the mouse model of bleomycin (BLM)-induced PF. Utilizing CDH11 knockout (Cdh11 -/-) mice and CDH11-neutralizing antibodies, we characterized the contribution of CDH11 in the BLM model. An alveolar epithelial cell line, A549, was used to investigate the role of CDH11 in EMT.
CDH11 expression was increased in patients with severe (1.6±0.1 D-ct) versus (vs) mild IPF (1.0±0.1 D-ct, p=0.004). CDH11 expression was localized to hyperplastic alveolar epithelial cells and alveolar macrophages in IPF patients and mice given BLM. Compared to wild type (WT), Cdh11 -/- mice given BLM showed reductions in histopathological evidence of lung fibrosis (Ashcroft score: WT 3.9±0.3 vs Cdh11 -/- 2.6±0.5, p=0.04) and reductions in soluble collagen (WT 342±41 mg/ml vs Cdh11 -/- 208±35 mg/ml, p=0.02). Furthermore, TGF-b levels were reduced in bronchoalveolar lavage (BAL) fluid (74±8 pg/ml) and BAL cell pellets (38±8 pg/ml) from Cdh11 -/- vs WT mice given BLM (214±11 BAL pg/ml, p<0.001) (106±16 cell pellet pg/ml, p=0.009). Similar reductions in lung fibrosis and TGF-b were obtained in WT mice given neutralizing CDH11 antibodies beginning 10 days after BLM. In vitro studies of A549 cells demonstrated Cdh11 upregulation by TGF-b and Cdh11 siRNA resulted in a reduction in EMT endpoints including TGF-b-induced collagen production and Snail2/Slug transcription.
We conclude that CDH11 contributes to pulmonary fibrosis through promotion of TGF-b production and the regulation of EMT. This suggests CDH11 may be a novel therapeutic target for PF.
To cite this abstract, please use the following information:
Schneider, Daniel J., Wu, Minghua, Le, Thuy T., Cho, Seo-Hee, Brenner, Michael B., Blackburn, Michael R., et al; Cadherin 11 Promotes Pulmonary Fibrosis through Production of TGF and the Regulation of Epithelial to Mesenchymal Transition. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :602