ABSTRACT
In interstitial fibrosis, alveolar epithelial type II (AE2) cells fail to repair damaged epithelium. However, whether this dysfunction is related to fibroblast growth factor (FGF) signal pathway and how it affects the fibrotic process remains unclear. In our study, the medium of the human foetal lung fibroblast cell line MRC-5 (Med) can induce epithelial-to-mesenchymal transition (EMT) in AE2 cells, we also found that TGF-ß in Med can induce FGF-2 and CTGF expression in AE2 cells. TGF-ß or CTGF exposure trigger a FGFR2 subtype b to c transition which can be supressed by siRNA-CTGF. All together, since FGFR2IIIc have the highest affinity with FGF-2 in all of the FGFRs, we indicate the activation of FGF2 signal pathway was induced by TGF-ß, which is the key component of Med Here, we also find the inhibitory effect of msFGFR2c (S252W mutant of soluble FGFR2IIIc extracellular domain) on EMT of mouse primary AE2 cells in pulmonary fibrotic process. In a bleomycin-induced mouse pulmonary fibrosis model, msFGFR2c alleviate pulmonary fibrosis and suppress the decrease in pro-SPC levels. Thus, msFGFR2c can inhibit EMT-induced fibrosis of AE2 cells via FGF-2 signal and AE2 cells is suggested to play an important role in the lung fibrotic process.
Subject(s)
Alveolar Epithelial Cells/metabolism , Epithelial-Mesenchymal Transition/physiology , Pulmonary Fibrosis/metabolism , Receptor, Fibroblast Growth Factor, Type 2/metabolism , Animals , Cell Line , Connective Tissue Growth Factor/metabolism , Culture Media, Conditioned/pharmacology , Disease Models, Animal , Fibroblasts/metabolism , Humans , Mice , Receptor, Fibroblast Growth Factor, Type 2/genetics , Signal Transduction , Transforming Growth Factor beta/metabolismABSTRACT
Nanoparticle-based pulmonary delivery of protein therapeutics provides a promising approach for improving protein bioavailability to treat either local or systemic diseases, however high-efficient nanocarrier is a great challenge. Here, biomimetic phosphorylcholine-chitosan nanoparticles (PCCs-NPs) taking advantages of both zwitterionic phosphorylcholine and chitosan were developed as a pulmonary protein delivery platform. msFGFR2c, a potential therapeutic protein for lung fibrosis as model was loaded into PCCs-NPs via ionic gelation. The obtained msFGFR2c/PCCs-NPs inhibited α-SMA expression in fibroblasts induced by TGF-ß1, slightly more effective than naked msFGFR2c. After orotracheal administration to bleomycin-induced pulmonary fibrosis model rats, msFGFR2c/PCCs-NPs resulted in a significant antifibrotic efficacy, with reduction in inflammatory cytokines and α-SMA expression, remarkable attenuation of lung fibrosis score and collagen deposition, and significant increase in survival rate, while naked msFGFR2c exhibited a poor efficacy. The in vitro and in vivo results strongly indicated that PCCs-NPs may be a promising nanocarrier for pulmonary protein delivery.
