Sequential expression of IGF-IB followed by active TGF-β1 induces synergistic pulmonary fibroproliferation in vivo

Andonegui G, Ni A, Leger C, Kelly MM, Wong JF, Jalloul A, Winston BW. Sequential expression of IGF-IB followed by active TGF-beta 1 induces synergistic pulmonary fibroproliferation in vivo. Am J Physiol Lung Cell Mol Physiol 303: L788-L798, 2012. First published August 24, 2012; doi:10.1152/ajplung.00008.2012.-Pulmonary fibrosis, 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 pulmonary fibrosis and fibroproliferative acute respiratory distress syndrome. However, we showed that IGF-I overexpression alone in wild-type mouse lungs does not cause fibroproliferation. We therefore questioned whether IGF-I, acting together with active TGF-beta 1, a known profibrotic cytokine, enhances pulmonary fibroproliferation caused by active TGF-beta 1. A unique sequential adenoviral transgene mouse model was used expressing AdEmpty/AdTGF-beta 1 or AdhIGF-IB/AdTGF-beta 1 transgenes. IGF-IB plus active TGF-beta 1 transgene expression synergistically increased collagen deposition in the lung parenchyma compared with active TGF-beta 1 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 expression, a marker of myofibroblast proliferation and differentiation, was also increased. Finally, fibroblasts exposed ex vivo to BALF isolated from AdhIGF-IB/AdTGF-beta 1-transduced mice showed synergistic collagen induction compared with BALF from AdEmpty/AdTGF-beta 1-transduced mice. This study provides the first direct evidence that IGF-I is able to synergistically enhance pulmonary fibroproliferation in cooperation with TGF-beta 1.