Abstract
Background: Disease-related injury in any organ triggers a complex cascade of cellular and molecular responses that culminate in tissue fibrosis, inflammation, and angiogenesis simultaneously. Multiple cell angiogenesis is an essential part of the tissue damage response, which is involved in fibrosis development. RC28-E is a novel recombinant dual decoy receptor lgG1 Fc-fusion protein that can block vascular endothelial growth factor (VEGFA), platelet-derived growth factor (PDGF), and fibroblast growth factor-2 (FGF-2) simultaneously. This protein has stepped into clinical trials (NCT03777254) for the treatment of pathological neovascularization-related diseases. Here, we report on the role of RC28-E during anti-fibrosis and its potential multitarget function in regulating fibrosis. Methods: A bleomycin-induced pulmonary fibrosis C57BL/6 mouse model was established. Hematoxylin and eosin staining (HE) and Masson staining (Masson’s) were performed to evaluate the pulmonary fibrosis based on the scoring from, Ashcroft score. Fibrosis related factors and inflammatory cytokines including HYP, α-SMA, procollagen, ICAM, IL-6, IL-1, and TNF-α were also determined at the protein and mRNA levels to characterize the fibrosis. Both mRNA and protein levels of VEGF, FGF, and transforming growth factor (TGF)-β were detected by quantitative real-time PCR (qRT-PCR) and immunohistochemical (IHC) analysis, respectively. Pulmonary fibrosis and related cytokines were re-evaluated in vivo after 3 doses of RC28-E (5 mg/kg, 15 mg/kg, and 50 mg/kg, ip. Tiw × 9) in comparison with a mono-target antagonist treatment (VEGF or FGF blocking). RC28-E attenuated the activation of TGF-β induced fibroblasts in vitro. Expression levels of α-SMA and collagen I, as well as proliferation and migration, were determined with the human skin fibroblast cell line Detroit 551 and primary murine pulmonary fibroblast cells. The mechanism of RC28-E via the TGF-β/Smad pathway was also investigated. Results: RC28-E exhibits significant anti-fibrosis effects on Idiopathic pulmonary fibrosis (IPF) in vivo. Moreover, TGF-β induced fibroblast activation in vitro via the inhibition of the TGF-β downstream Smad pathway, thus providing potential therapeutics for clinical disease-related fibrosis-like IPF as well as chemotherapy-induced fibrosis in cancer therapy.
Highlights
Fibrosis and resulting organ failures account for at least one-third of the world’s death toll [1].The repair response following tissue damage allows protecting the relative integrity of tissues and organs
The results showed that the expression of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), and transforming growth factor (TGF)-β was null in control lung tissues while they were up-regulated during pulmonary fibrosis
Comparable results were obtained when α-smooth muscle actin (α-SMA) and collagen I were analyzed at the transcription level (Figure 6C,D). These results showed that RC28-E significantly decreased the expression of both α-SMA and collagen I, indicating that TGF-β1-induced fibroblast activation was significantly attenuated by RC28-E, while these effects were more pronounced with RC28-E compared to RC28-C1 (VEGF-trap) and RC28-C2 (FGF-trap)
Summary
Fibrosis and resulting organ failures account for at least one-third of the world’s death toll [1].The repair response following tissue damage allows protecting the relative integrity of tissues and organs. Bevacizumab, a full-length humanized monoclonal antibody designed against all types of VEGF, was approved by the FDA in 2004 for the treatment of metastatic diseases and colon or rectal cancers [19] This medicine was reported to hamper the activation of hepatocytes and the proliferation of hepatic stellate cells (HSCs) by blocking the effect of VEGF on HSCs, which could attenuate the development of hepatic fibrosis [20]. RC28-E is a novel recombinant dual decoy receptor lgG1 Fc-fusion protein that can block vascular endothelial growth factor (VEGFA), platelet-derived growth factor (PDGF), and fibroblast growth factor-2 (FGF-2) simultaneously This protein has stepped into clinical trials (NCT03777254) for the treatment of pathological neovascularization-related diseases. Methods: A bleomycin-induced pulmonary fibrosis C57BL/6 mouse model was established
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
