[Show abstract][Hide abstract] ABSTRACT: Background: Pulmonary fibrosis (PF), the end stage of a variety of fibroproliferative lung diseases, is usually induced after repetitive or chronic lung injury or inflammation. The mechanisms of fibroproliferation are poorly understood. Insulin-like Growth Factor-I (IGF-I) is significantly elevated in patients with PF and fibroproliferative acute respiratory distress syndrome (ARDS). However, we showed that IGF-I overexpression alone in wild-type mouse lungs does not cause fibroproliferation. We, therefore, questioned if IGF-I, acting together with active TGF-β1, a known profibrotic cytokine, enhances pulmonary fibroproliferation caused by active TGF-β1. Methods: A unique sequential adenoviral transgene mouse model was used expressing AdEmpty/AdTGF-β1 or AdhIGF-IB/AdTGF-β1 transgenes. Results: IGF-IB plus active TGF-β1 transgene expression synergistically increased collagen deposition in the lung parenchyma compared to active TGF-β1 expression alone. The enhanced fibrosis was accompanied by an increased recruitment of macrophages and lymphocytes into the bronchoalveolar lavage fluid (BALF) and inflammatory cells in the lungs. Alpha smooth muscle actin (α-SMA) expression, a marker of myofibroblast proliferation and differentiation, was also increased. Finally, fibroblasts exposed ex vivo to BALF isolated from AdhIGF-IB/AdTGF-β1 transduced mice showed synergistic collagen induction when compared to BALF from AdEmpty/AdTGF-β1 transduced mice. Conclusion: This study provides the first direct evidence that IGF-I is able to synergistically enhance pulmonary fibroproliferation in co-operation with TGF-β1.
Preview · Article · Aug 2012 · AJP Lung Cellular and Molecular Physiology
[Show abstract][Hide abstract] ABSTRACT: Pulmonary fibrosis (PF), the end stage of a variety of fibroproliferative lung diseases, is characterized by excessive lung mesenchymal cell activation and extracellular matrix deposition. Most PF is induced after repetitive or chronic lung inflammation; however, a significant portion of PF occurs without apparent inflammation. The mechanisms of fibroproliferation are poorly understood. Studies have shown that cytokines regulating inflammation and tissue repair processes play essential roles in the development of PF. Insulin-like growth factor I (IGF-I) has been shown to stimulate lung mesenchymal cell proliferation and extracellular matrix synthesis in vitro and is significantly elevated in patients with PF. In this study, we investigated whether human IGF-IB (hIGF-IB) expression in the lungs induces PF in a C57BL/6 mouse model. Mice were subjected to adenoviral gene transfer, and the effects of hIGF-IB expression on the lungs were examined 3, 7, 14, 21, and 42 days after gene delivery. hIGF-IB expression induced significant and prolonged inflammatory cell infiltration into the lungs, with an early neutrophil infiltration followed by a late macrophage infiltration. No significant fibroblast or matrix accumulation could be detected in the lungs of these mice. No significant collagen accumulation could be detected in vivo, despite in vitro evidence that hIGF-IB induces collagen mRNA expression in fibroblasts. Therefore, IGF-IB alone is not sufficient to induce fibrosis, and it is possible that a coactivator is required to induce significant fibroproliferation in vivo.