Pharmacology Study of the Multiple Angiogenesis Inhibitor RC28-E on Anti-Fibrosis in a Chemically Induced Lung Injury Model

Kou, Xiangying; Sun, Yeying; Li, Shenjun; Bian, Weihua; Liu, Zhihao; Zhang, Daolai; Jiang, Jing

doi:10.3390/biom9110644

Cited by 4 publications

(4 citation statements)

References 51 publications

(53 reference statements)

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“…Besides accelerating regeneration in the injured liver, FGF signaling also leads to fibrosis development. There is evidence that as a commonly used model of chronic liver injury, carbon tetrachloride (CCl4)-induced liver fibrosis is significantly reduced in FGF1/FGF2-deficient mice (Kou et al, 2019). Consistently, inhibition of FGF signaling blunts inflammatory through restraining activation of the NF-κB signaling cascades in several experimental models for chronic inflammatory diseases (Huang et al, 2019;Qi and Xin, 2019).…”

Section: Introductionmentioning

confidence: 98%

Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells

Zhang

et al. 2020

Front. Cell Dev. Biol.

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It is a well-documented event that fibroblast growth factors (FGFs) regulate liver development and homeostasis in autocrine, paracrine, and endocrine manners via binding and activating FGF receptors (FGFRs) tyrosine kinase in hepatocytes. Recent research reveals that hepatic stellate cells (HSCs) play a fundamental role in liver immunology. However, how FGF signaling in HSCs regulates liver inflammation remains unclear. Here, we report that FGF promoted NF-κB signaling, an inflammatory pathway, in human HSCs, which was associated with FGFR1 expression. Both FGF and NF-κB signaling in HSCs were compromised by FGFR1 tyrosine kinase inhibitor. After stimulating HSCs with proinflammatory cytokines, expression of multiple FGF ligands was significantly increased. However, disruption of FGF signaling with FGFR inhibitors prominently reduced the apoptosis, inflammatory response, NF-κB nuclear translocation, and expression of matrix metalloproteinase-9 (MMP-9) induced by TNFα in HSCs. Interestingly, FGF21 significantly alleviated the inflammation responses in the concanavalin A (Con A)-induced acutely injured liver. Unlike canonic FGFs that elicit signals through activating the FGFR-heparan sulfate complex, FGF21 activates the FGFR-KLB complex and elicits a different set of signals. Therefore, the finding here indicates the urgency of developing pathway-specific inhibitors that only suppress canonical FGF, but not non-canonical FGF21, signaling for alleviating inflammation in the liver, which is presented in all stages of diseased liver.

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Section: Introductionmentioning

confidence: 98%

Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells

Zhang

et al. 2020

Front. Cell Dev. Biol.

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“…The second stage is the pulmonary fibrosis stage. Interstitial cell proliferation and matrix collagen aggregation replace normal lung tissue structure (25,26). Studies have shown that the presence of myofibroblasts in fibroblast lesions is one of the histopathological markers of pulmonary fibrosis, which is induced by many chemokines, the most common of which is TGF-β (27,28).…”

Section: Discussionmentioning

confidence: 99%

Total alkaloids of bulbus of Fritillaria cirrhosa alleviate bleomycin-induced inflammation and pulmonary fibrosis in rats by inhibiting TGF-β and NF-κB signaling pathway

Pai,

Er-bu,

et al. 2023

Food & Nutrition Research

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Background: Bulbus of Fritillaria cirrhosa is a medicinal and edible plant that has the functions of clearing away heat and moisturizing the lungs, resolving phlegm, and relieving coughs. Its ethanol extract has been proven to have a therapeutic effect on lung diseases. Pulmonary fibrosis is a respiratory disease that forms scars in lung tissue, leading to severe respiratory problems. However, the therapeutic effect of total alkaloids of bulbus of Fritillaria cirrhosa (BFC-TA) on pulmonary fibrosis has not been confirmed. Objective: This study aimed to investigate the therapeutic effect of total alkaloids of Fritillaria cirrhosa on pulmonary fibrosis rat model and explore its potential mechanism. Design: The total alkaloids in the bulbus of Fritillaria cirrhosa were purified using cation exchange resin. The alkaloids contained in the BFC-TA were identified, and the concentration of alkaloids was determined by High Performance Liquid Chromatography-Diode Array Detector-Evaporative Light Scattering Detector (HPLC-DAD-ELSD). Bleomycin (BLM) (5.0 mg/kg) was instilled into the trachea of 60 rats to establish a pulmonary fibrosis model. After 7 days, BFC-TA (34.2, 68.4, and 136.8 mg/kg) was administered continuously for 21 days. During this period, the body weight changes of the rats were measured, the levels of hydroxyproline (HYP) and inflammatory factors were measured in the collected serum, and the histological analysis of the lung tissue was performed by staining technology. Western blotting and quantitative Polymerase Chain Reaction (qPCR) were used to assess the protein and gene composition of inflammation and transforming growth factor-β (TGF-β) signaling pathways. Results: Nine main components (Peimisine, Imperialine-3-β-D-glucoside, Yibeinoside A, Imperialine, Peiminine, Isopeimine, Hupehenine, Delavinone, Ebeiedinone) were determined by HPLC-DAD-ELSD, and the contents of Peimisine, Imperialine-3-β-D-glucoside and Imperialine were determined. BFC-TA (34.2, 68.4, and 136.8 mg/kg) reduced the levels of pro-inflammatory factors, increased the levels of anti-inflammatory factors, dose-dependently improved the morphology of lung tissue. And during epithelial-mesenchymal transition process, BFC-TA dose-dependently reduced the expression of E-cadherin, dose-dependently increased the expression of Fibronectin. In addition, Western blot analysis and qPCR results showed that inhibiting NF-κB and TGF-β-related signaling pathways effectively slowed down the occurrence of BLM-induced pulmonary fibrosis in rats. And the therapeutic effect of BFC-TA (136.8 mg/kg) is better than that of pirfenidon (PFD) (150 mg/kg). Conclusion: BFC-TA effectively alleviates the progression of the BLM-induced pulmonary fibrosis rat model by regulating the inflammatory response in the lungs and the expression of the TGF-β signaling pathway.

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“…Quantitative Real time PCR was performed as previously described [ 21 ]. Total RNA was extracted from cultivated cells using Trizol reagent (Thermo Fisher, USA).…”

Section: Methodsmentioning

confidence: 99%

Prolyl oligopeptidase inhibition ameliorates experimental pulmonary fibrosis both in vivo and in vitro

Cucinotta,

Mannino,

Casili

et al. 2023

Respir Res

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Background Pulmonary fibrosis is a progressive disease characterized by lung remodeling due to excessive deposition of extracellular matrix. Although the etiology remains unknown, aberrant angiogenesis and inflammation play an important role in the development of this pathology. In this context, recent scientific research has identified new molecules involved in angiogenesis and inflammation, such as the prolyl oligopeptidase (PREP), a proteolytic enzyme belonging to the serine protease family, linked to the pathology of many lung diseases such as pulmonary fibrosis. Therefore, the aim of this study was to investigate the effect of a selective inhibitor of PREP, known as KYP-2047, in an in vitro and in an in vivo model of pulmonary fibrosis. Methods The in vitro model was performed using human alveolar A549 cells. Cells were exposed to lipopolysaccharide (LPS) 10 μg/ml and then, cells were treated with KYP-2047 at the concentrations of 1 μM, 10 μM and 50 μM. Cell viability was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) bromide colorimetric assay, while inflammatory protein expression was assessed by western blots analysis. The in vivo model was induced in mice by intra-tracheal administration of bleomycin (1 mg/kg) and then treated intraperitoneally with KYP-2047 at doses of 1, 2.5 and 5 mg/kg once daily for 12 days and then mice were sacrificed, and lung tissues were collected for analyses. Results The in vitro results demonstrated that KYP-2047 preserved cell viability, reduced inflammatory process by decreasing IL-18 and TNF-α, and modulated lipid peroxidation as well as nitrosative stress. The in vivo pulmonary fibrosis has demonstrated that KYP-2047 was able to restore histological alterations reducing lung injury. Our data demonstrated that KYP-2047 significantly reduced angiogenesis process and the fibrotic damage modulating the expression of fibrotic markers. Furthermore, KYP-2047 treatment modulated the IκBα/NF-κB pathway and reduced the expression of related pro-inflammatory enzymes and cytokines. Moreover, KYP-2047 was able to modulate the JAK2/STAT3 pathway, highly involved in pulmonary fibrosis. Conclusion In conclusion, this study demonstrated the involvement of PREP in the pathogenesis of pulmonary fibrosis and that its inhibition by KYP-2047 has a protective role in lung injury induced by BLM, suggesting PREP as a potential target therapy for pulmonary fibrosis. These results speculate the potential protective mechanism of KYP-2047 through the modulation of JAK2/STAT3 and NF-κB pathways. Graphical abstract

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Pharmacology Study of the Multiple Angiogenesis Inhibitor RC28-E on Anti-Fibrosis in a Chemically Induced Lung Injury Model

Cited by 4 publications

References 51 publications

Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells

Disruption of FGF Signaling Ameliorates Inflammatory Response in Hepatic Stellate Cells

Total alkaloids of bulbus of Fritillaria cirrhosa alleviate bleomycin-induced inflammation and pulmonary fibrosis in rats by inhibiting TGF-β and NF-κB signaling pathway

Prolyl oligopeptidase inhibition ameliorates experimental pulmonary fibrosis both in vivo and in vitro

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