Abnormal expression of IGF-binding proteins, an initiating event in idiopathic pulmonary fibrosis?

For significant improvements to occur in the survival of patients with idiopathic pulmonary fibrosis (IPF), it is necessary to develop novel and more precisely targeted therapies. The selection of future appropriate regimens must critically depend on improved characterization of the molecules driving the pathogenesis of IPF. It is well defined that IPF is characterized by the expression of genes indicating an active tissue remodeling program, including extracellular matrix (ECM) and basement membrane components, as well as myofibroblast-associated and epithelial cell-related genes. A few recent advances are worth mentioning. Pulmonary research demonstrates abnormal expression of insulin-like growth factor (IGF) binding proteins (IGFBPs) in IPF, including human IPF bronchoalveolar lavage (BAL) cells and BAL fluids, human IPF fibroblasts, as well as fibrotic lung tissues of bleomycin-induced mice and IPF patients, analyzed by microarray, reverse transcription-polymerase chain reaction (RT-PCR), ribonuclease protection assay (RPA), Western blot, immunohistochemistry, or enzyme-linked immunosorbent assay (ELISA). Simultaneously, in vitro and in vivo studies indicate the involvement of IGFBPs in the initiation and development of the fibrosis process, including fibroblast activation and transdifferentiation to a myofibroblast phenotype, epithelial-mesenchymal transition (EMT), increased ECM production, and decreased ECM degradation, possibly contributing to the final lung fibrosis. These observations suggest that dysregulation of IGFBPs may be a key factor responsible for the initiation and perpetuation of IPF. Such efforts could lead to potential candidate molecules being exploited for therapeutic manipulation.