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. 2019 Jan 3:2019:2710509.
doi: 10.1155/2019/2710509. eCollection 2019.

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

Lihong Meng  1 , Xiaomei Zhang  2 , Hong Wang  3   4 , Huan Dong  1 , Xiaofeng Gu  1 , Xiaolin Yu  1 , Yushan Liu  1
Affiliations

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

Lihong Meng et al. Evid Based Complement Alternat Med. .

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.

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Figures

Figure 1
Figure 1
H&E staining of lung tissues (100x). (a) Control group treated by normal saline on days 14. (b) Control group treated by normal saline on days 28. (c) BLM group induced pulmonary fibrosis and treated by normal saline on days 14. (d) BLM group induced into pulmonary fibrosis and treated by normal saline on days 28. (e) BLM + Pred group treated by prednisone on days 14. (f) BLM + Pred group treated by prednisone on days 28. (g) BLM + YYYQ-L group treated by low dose of YYYQ on days 14. (h) BLM + YYYQ-L group treated by low dose of YYYQ on days 28. (i) BLM + YYYQ-M group treated by middle dose of YYYQ on days 14. (j) BLM + YYYQ-M group treated by middle dose of YYYQ on days 28. (k) BLM + YYYQ-H group treated by high dose of YYYQ on days 14. (l) BLM + YYYQ-H group treated by high dose of YYYQ on days 28.
Figure 2
Figure 2
Scores of alveolitis.
Figure 3
Figure 3
Masson's staining of lung tissues (200x). (a) Control group treated by normal saline on days 14. (b) Control group treated by normal saline on days 28. (c) BLM group induced pulmonary fibrosis and treated by normal saline on days 14. (d) BLM group induced into pulmonary fibrosis and treated by normal saline on days 28. (e) BLM + Pred group treated by prednisone on days 14. (f) BLM + Pred group treated by prednisone on days 28. (g) BLM + YYYQ-L group treated by low dose of YYYQ on days 14. (h) BLM + YYYQ-L group treated by low dose of YYYQ on days 28. (i) BLM + YYYQ-M group treated by middle dose of YYYQ on days 14. (j) BLM + YYYQ-M group treated by middle dose of YYYQ on days 28. (k) BLM + YYYQ-H group treated by high dose of YYYQ on days 14. (l) BLM + YYYQ-H group treated by high dose of YYYQ on days 28.
Figure 4
Figure 4
Scores of pulmonary fibrosis.
Figure 5
Figure 5
The secreted protein levels of TGF-β1, CTGF, interleukin 18, and hydroxyproline in each group of rats on days 14 and 28.
Figure 6
Figure 6
The mRNA expression of α-SMA, E-cadherin, laminin, and collagen I in each group of rats on days 14 and 28.
Figure 7
Figure 7
The mRNA expression of TGF-β1, TβRI, TβRII, Smad3, and Smad7 in each group of rats on days 14 and 28.
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