Abstract
Idiopathic pulmonary fibrosis (IPF) is an important public health problem, and it has few treatment options given its poorly understood etiology; however, epithelial to mesenchymal transition (EMT) of pneumocytes has been implicated as a factor. Herein, we aimed to explore the underlying mechanisms of lung fibrosis mediated by EMT, with a focus on the alternative splicing of fibroblast growth factor receptor 2 (FGFR2), using bleomycin (BLM)-induced lung fibrotic and transgenic mouse models. We employed BLM-induced and surfactant protein C (SPC)-Cre and LacZ double transgenic mouse models. The results showed that EMT occurred during lung fibrosis. BLM inhibited the expression of epithelial splicing regulatory protein 1 (ESRP1), resulting in enhanced alternative splicing of FGFR2 to the mesenchymal isoform IIIc. BLM-induced lung fibrosis was also associated with the activation of TGF-β/Smad signaling. These findings have implications for rationally targetted strategies to therapeutically address IPF.
Highlights
As its name suggests, idiopathic pulmonary fibrosis (IPF), a form of chronic, progressive, interstitial lung disease with a characteristic histopathological pattern of usual interstitial pneumonia [1], is a disease whose cause is poorly understood
After we observed epithelial to mesenchymal transition (EMT) during the course of lung fibrosis, we explored the possible mechanisms of EMT with a focus on alternative splicing
Considerable efforts have been devoted to understanding the factors involved in the etiology and pathogenesis of IPF, such as occupational and environmental exposure, tobacco consumption, gastroesophageal reflux, genetic factors, and pathologically activated molecular pathways, the understanding of the pathogenesis of IPF is still incomplete
Summary
Idiopathic pulmonary fibrosis (IPF), a form of chronic, progressive, interstitial lung disease with a characteristic histopathological pattern of usual interstitial pneumonia [1], is a disease whose cause is poorly understood. IPF is the most common form of idiopathic interstitial pneumonia, with an estimated incidence of approximately 5–18 per 100000 [1,2,3]. The estimated prevalence of IPF is 1–63 per 100000 people, depending on the diagnostic criteria applied and the geographic location [1,4,5]. There is evidence that reactivation of developmental signaling pathways leads to alveolar epithelial cell damage, resulting in IPF [3,7,8].
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