Basic Science
Abstract # 733: Alveolar Epithelial Cell Injury Triggers Lung Fibrosis in a Mouse Model of Scleroderma
Authors: Rachel K. Hoyles, Korsa Khan, Xu Shiwen, Gisela E. Lindahl, Patricia Garcia, Athol U. Wells, Carol M. Black, David J. Abraham, Christopher P. Denton. Royal Free and University College Medical School, London, United Kingdom; Centre for Rheumatology, Royal Free and University College Medical School, London, United Kingdom
Objective: One of the hallmarks of the diffuse scleroderma phenotype is the development of interstitial lung disease (ILD). However, the mechanism behind this association remains unclear. Perturbations in the TGF-signaling pathway have been implicated in the pathogenesis of scleroderma in general, and mice with fibroblast-specific defects in TGF-signaling develop both scleroderma and ILD. The authors thus postulated that these fibroblast-specific defects might explain the increased susceptibility to lung injury and fibrosis both in this model and in human disease.
Methods: Transgenic (TG) affected mice and non-affected controls were treated with intra-tracheal bleomycin to induce ILD, and were then sacrificed at various time points. The lungs were examined histologically, and tissue lysates were probed biochemically for evidence of perturbations in connective tissue components.
Results: The TGF-transgenic mice had evidence at baseline of lung epithelial layer structural abnormalities, similar to the defects caused in WT mice by bleomycin treatment. When the TG mice were treated with bleomycin, they developed marked pulmonary inflammation and tissue remodeling. Collagen mRNA and protein levels were increased in the TG animals compared to the controls.
Significance: This study demonstrates that altered TGF-signaling in pulmonary fibroblasts might lead to altered aleveolar epithelial cell structure at baseline, and might explain the exaggerated response to other pro-fibrotic stimuli in vivo. This study suggests that targeting the TGF signaling pathway in vivo early in the disease course in scleroderma patients might be beneficial not only for the prevention of skin fibrosis, but also for the prevention of ILD, a major cause of death in patients with scleroderma.
