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CLC number: R563.9

On-line Access: 2015-01-05

Received: 2014-08-18

Revision Accepted: 2014-10-09

Crosschecked: 2014-12-24

Cited: 6

Clicked: 2715

Citations:  Bibtex RefMan EndNote GB/T7714

 ORCID:

Jiang-hua CHEN

http://orcid.org/0000-0002-3282-3998

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Journal of Zhejiang University SCIENCE B 2015 Vol.16 No.1 P.52-61

http://doi.org/10.1631/jzus.B1400229


Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice


Author(s):  Xue Shao, Meng Li, Chong Luo, Ying-ying Wang, Ying-ying Lu, Shi Feng, Heng Li, Xia-bing Lang, Yu-cheng Wang, Chuan Lin, Xiu-jin Shen, Qin Zhou, Hong Jiang, Jiang-hua Chen

Affiliation(s):  Kidney Disease Center, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China

Corresponding email(s):   chenjianghua@zju.edu.cn

Key Words:  Paraquat, Pulmonary fibrosis, Rapamycin, Transforming growth factor-β, 1, α, -Smooth muscle actin, Methylprednisolone


Xue Shao, Meng Li, Chong Luo, Ying-ying Wang, Ying-ying Lu, Shi Feng, Heng Li, Xia-bing Lang, Yu-cheng Wang, Chuan Lin, Xiu-jin Shen, Qin Zhou, Hong Jiang, Jiang-hua Chen. Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice[J]. Journal of Zhejiang University Science B, 2015, 16(1): 52-61.

@article{title="Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice",
author="Xue Shao, Meng Li, Chong Luo, Ying-ying Wang, Ying-ying Lu, Shi Feng, Heng Li, Xia-bing Lang, Yu-cheng Wang, Chuan Lin, Xiu-jin Shen, Qin Zhou, Hong Jiang, Jiang-hua Chen",
journal="Journal of Zhejiang University Science B",
volume="16",
number="1",
pages="52-61",
year="2015",
publisher="Zhejiang University Press & Springer",
doi="10.1631/jzus.B1400229"
}

%0 Journal Article
%T Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice
%A Xue Shao
%A Meng Li
%A Chong Luo
%A Ying-ying Wang
%A Ying-ying Lu
%A Shi Feng
%A Heng Li
%A Xia-bing Lang
%A Yu-cheng Wang
%A Chuan Lin
%A Xiu-jin Shen
%A Qin Zhou
%A Hong Jiang
%A Jiang-hua Chen
%J Journal of Zhejiang University SCIENCE B
%V 16
%N 1
%P 52-61
%@ 1673-1581
%D 2015
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1400229

TY - JOUR
T1 - Effects of rapamycin against paraquat-induced pulmonary fibrosis in mice
A1 - Xue Shao
A1 - Meng Li
A1 - Chong Luo
A1 - Ying-ying Wang
A1 - Ying-ying Lu
A1 - Shi Feng
A1 - Heng Li
A1 - Xia-bing Lang
A1 - Yu-cheng Wang
A1 - Chuan Lin
A1 - Xiu-jin Shen
A1 - Qin Zhou
A1 - Hong Jiang
A1 - Jiang-hua Chen
J0 - Journal of Zhejiang University Science B
VL - 16
IS - 1
SP - 52
EP - 61
%@ 1673-1581
Y1 - 2015
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1400229


Abstract: 
Background and aims: Ingestion of paraquat (PQ), a widely used herbicide, can cause severe toxicity in humans, leading to a poor survival rate and prognosis. One of the main causes of death by PQ is PQ-induced pulmonary fibrosis, for which there are no effective therapies. The aim of this study was to evaluate the effects of rapamycin (RAPA) on inhibiting PQ-induced pulmonary fibrosis in mice and to explore its possible mechanisms. Methods: Male C57BL/6J mice were exposed to either saline (control group) or PQ (10 mg/kg body weight, intraperitoneally; test group). The test group was divided into four subgroups: a PQ group (PQ-exposed, non-treated), a PQ+RAPA group (PQ-exposed, treated with RAPA at 1 mg/kg intragastrically), a PQ+MP group (PQ-exposed, treated with methylprednisolone (MP) at 30 mg/kg intraperitoneally), and a PQ+MP+RAPA group (PQ-exposed, treated with MP at 30 mg/kg intraperitoneally and with RAPA at 1 mg/kg intragastrically). The survival rate and body weight of all the mice were recorded every day. Three mice in each group were sacrificed at 14 d and the rest at 28 d after intoxication. Lung tissues were excised and stained with hematoxylin-eosin (H&E) and Masson 19;s trichrome stain for histopathological analysis. The hydroxyproline (HYP) content in lung tissues was detected using an enzyme-linked immunosorbent assay (ELISA) kit. The expression of transforming growth factor-β;1 (TGF-β1) and ;1;-Smooth muscle actin (;1;-SMA) in lung tissues was detected by immunohistochemical staining and Western blotting. Results: A mice model of PQ-induced pulmonary fibrosis was established. Histological examination of lung tissues showed that RAPA treatment moderated the pathological changes of pulmonary fibrosis, including alveolar collapse and interstitial collagen deposition. HYP content in lung tissues increased soon after PQ intoxication but had decreased significantly by the 28th day after RAPA treatment. Immunohistochemical staining and Western blotting showed that RAPA treatment significantly down-regulated the enhanced levels of TGF-β1 and ;1;-SMA in lung tissues caused by PQ exposure. However, RAPA treatment alone could not significantly ameliorate the lower survival rate and weight loss of treated mice. MP treatment enhanced the survival rate, but had no significant effects on attenuating PQ-induced pulmonary fibrosis or reducing the expression of TGF-β1 and ;1;-SMA. Conclusions: This study demonstrates that RAPA treatment effectively suppresses PQ-induced alveolar collapse and collagen deposition in lung tissues through reducing the expression of TGF-β1 and ;1;-SMA. Thus, RAPA has potential value in the treatment of PQ-induced pulmonary fibrosis.

雷帕霉素对小鼠百草枯中毒导致肺纤维化的治疗作用

目的:评估雷帕霉素(RAPA)对小鼠百草枯(PQ)中毒导致肺纤维化的治疗作用,并初步探讨其作用机制。
创新点:首次在小鼠PQ中毒的模型中证明RAPA可明显抑制肺纤维化,且此作用与转化生长因子-β1(TGF-β1)的抑制相关。
方法:将C57BL/6J雄鼠分为对照组(腹腔注射生理盐水)和实验组(腹腔注射10mg/kgPQ)。实验组根据采用的治疗不同,可分为以下四组:PQ组、PQ+RAPA组、PQ+MP(甲强龙)组和PQ+MP+RAPA组。用苏木精-伊红染色法(HE)和马松(Masson)三色染色法观察肺组织病理结构变化,用酶联免疫吸附测定(ELISA)试剂盒检测肺组织中的羟脯氨酸(HYP)含量,用免疫组化和免疫印迹的方法检测TGF-β1和α-平滑肌肌动蛋白(α-SMA)的表达水平。
结论:本实验中小鼠的肺组织病理染色结果显示,RAPA治疗能缓解肺纤维化导致的病理改变(图3)。ELISA实验结果显示,RAPA治疗28天后可显著降低肺组织中HYP的含量(图4)。免疫组化和免疫印迹实验结果显示,RAPA治疗能明显下调肺组织中TGF-β1和α-SMA的高表达(图5和6)。综上所述,RAPA在治疗PQ中毒导致的肺纤维化中有重要价值。

关键词:百草枯;肺纤维化;雷帕霉素;甲强龙;转化生长因子-β1

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

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