Yangyin Yiqi Mixture Ameliorates Bleomycin-Induced Pulmonary Fibrosis in Rats through Inhibiting TGF-β1/Smad Pathway and Epithelial to Mesenchymal Transition

Abstract

Objective The aim of the current study was to investigate the protective effect of Yangyin Yiqi Mixture (YYYQ) on Bleomycin-induced pulmonary fibrosis in rats based on TGF-β1/Smad signal pathway and epithelial to mesenchymal transition (EMT). Methods 120 Wistar rats were randomly divided into six groups: control group, BLM group, BLM + Pred group, BLM+YYYQ-L group, BLM+YYYQ-M group, and BLM+YYYQ-H group. Rats were given an intratracheal instillation of 3 mg/kg BLM to establish the pulmonary fibrosis model and followed by different dosages of YYYQ (11, 22, 44g/kg, via intragastric gavage) or prednisone soluble (4.2mg/kg, via intragastric gavage) or water. After 14 days and 28 days, tissue sections were stained with hematoxylin-eosin and Masson's trichrome to observe histopathological changes. Protein levels of TGF-β1, CTGF, Interleukin 18, and hydroxyproline were detected by ELISA method, and mRNA expressions of TGF-β1, TβRI, TβRII, Smad3, Smad7, α-SMA, E-cadherin, laminin, and collagen I were detected by RT-PCR. Results TGF-β1, CTGF, Interleukin 18, and hydroxyproline levels and mRNA expression of TGF-β1, TβRI, TβRII, Smad3, α-SMA, laminin, and collagen I were significantly increased (p <0.01), while Smad7 and E-cadherin levels were significantly decreased in BLM group (p <0.01). YYYQ-M and YYYQ-H group had downregulated the TGF-β1, CTGF, hydroxyproline contents, and mRNA expression of TGF-β1, TβRI, TβRII, Smad3, α-SMA, laminin, and collagen I and upregulated mRNA levels of Smad7 and E-cadherin significantly (p <0.01 or p <0.05). The result from the present study, which was also supported by histological evidence, suggested that YYYQ-M group and YYYQ-H group exhibited better treatment effect on Bleomycin-induced pulmonary fibrotic rats when compared to that of BLM + Pred group (p <0.01). Meanwhile, the effect of YYYQ, in three different dosages, on the level of interleukin 18 was not significant. Conclusion These results showed that YYYQ has the potential of ameliorating the progression of pulmonary fibrosis, and the mechanism may be related to suppressing TGF-β1/Smad signal pathway and EMT in BLM-induced pulmonary fibrosis of rats.

Modulation of bleomycin‐induced oxidative stress and pulmonary fibrosis by N‐acetylcysteine in rats via AMPK/SIRT1/NF‐κβ

“…The development of fibrosis can be seen biochemically and histologically. The results of histopathological analysis showed that the main pathological manifestations of lung tissues were marked by collagen deposition, congested blood capillaries and alveolitis, which developed into pulmonary fibrosis 19,23 . The increased mitochondrial ROS, the disrupted membrane potential, the congested blood capillaries and alveolitis, and collagen deposition caused by BLM were also mitigated upon concurrent treatment with NAC.…”

“…TGF‐β1, a profibrotic factor, plays an important role in resulting multiple organ fibrosis through increasing the production of glucose and proteoglycans, promoting the transport of amino acids and the deposition of extracellular matrix 23 . During the process of pulmonary fibrosis, the increase of TGF‐β1 induces the up regulation of CTGF, which promotes the proliferation and differentiation of fibroblasts and collagen production 24 .…”

Role of nuclear factor-kappa B in bleomycin induced pulmonary fibrosis and the probable alleviating role of ginsenoside: histological, immunohistochemical, and biochemical study

“…Additionally, collapsed alveoli may be also due to vascular congestion and depletion of the pulmonary surfactant [ 40 , 41 ]. However, the presence of dilated alveoli could be result of epithelial, endothelial and basement membrane damage [ 42 , 43 ].…”

Natural Product-Based Potential Therapeutic Interventions of Pulmonary Fibrosis

“…In comparison, YYYQ induced the expression of Smad7 and E-cadherin in the BLM group and the prednisolone-treated BLM group. Therefore, it was supposed to be related to suppressing the EMT and TGF-β1/Smad signaling pathways [ 229 ]. Total alkaloids from Alstonia Scholaris (L.) R. Br.…”

“…This also enhanced the activity of SOD in the serum and lung tissues. Moreover, the alkaloid treatment resulted in decreased TGF-β and MMP-1 expressions [ 229 ]. Ophiocordyceps lanpingensis polysaccharides (OLP) alleviated collagen deposition and oxidative stress and decreased macrophage accumulation.…”