Protective effects and mechanism of astaxanthin on paraquat poisoning-induced pulmonary fibrosis in rats
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摘要:
目的：观察虾青素（astaxanthin，AX）对百草枯（paraquat，PQ）诱导大鼠肺纤维化的影响，并进一步探讨肺纤维化可能的发病机制。方法：SD大鼠随机分为正常对照组、PQ模型组及虾青素干预组。模型组及干预组大鼠腹腔注射百草枯造模后，干预组第2天起给予虾青素灌胃，对照组及模型组给予相应溶剂。分别于给药后第7、14、28 天处死大鼠，测定大鼠血清中羟脯氨酸（hydroxyproline，HYP）、基质金属蛋白酶（matrix metalloproteinase，MMP）1、MMP2、MMP9和基质金属蛋白酶组织抑制剂（tissue inhibitor of matrix metalloproteinase1， TIMP1）的含量，取固定部位肺组织切片行HE、Masson染色进行病理学观察，免疫组化法测定转化生长因子-β1（TGF-β1）的含量，对病理图像进行形态学测量分析。结果：①HE染色及Masson染色结果显示：干预组纤维化炎症程度明显低于模型组；②模型组大鼠中毒后羟脯氨酸较正常组增高（P<0.05），虾青素干预后，大鼠鼠肺血清羟脯氨酸水平较模型组降低（P<0.05）；③PQ模型组在肺纤维化区域TGF-β1弱阳性表达，虾青素干预后，TGF-β1表达含量下降，第28天最为明显，差异有统计学意义（P<0.05）；④模型组与干预组MMP1、MMP2、MMP9表达含量均较正常对照组升高。MMP1、MMP2、MMP9在PQ中毒后表达量逐渐升高，第14天达到高峰后下降，但第28天含量仍高于对照组。与模型组相比，干预组MMP2、MMP9含量均有下降，第14、28天显著，其差异有统计学意义（P<0.05）。TIMP1在干预期间与模型组及对照组无显著差异。结论：虾青素能够减弱肺纤维化大鼠肺组织病理的胶原沉积、减少肺组织中羟脯氨酸的含量、降低肺血清中MMP2、MMP9的含量，抑制肺组织中TGF-β1的分泌，从而减轻PQ引起的大鼠肺纤维化。
Abstract:
Objective：To observe the effects of astaxanthin on paraquat poisoning-induced pulmonary fibrosis in SD rats， and explore the mechanism of pulmonary fibrosis. Methods：The rats were randomly divided into three groups， including the normal control group， the PQ model group， and the astaxanthin group. The PQ group and the astaxanthin group were intraperitoneal injected with PQ. In the next day， the rats were treated by intragastric administration once a day. The control group and the PQ group were treated by the same dosage of solvent． On day 7， day 14， day 28 after treatment， the rats in each group were sacrificed. The levels of hydroxyproline （HYP） and TGF-β1 were measured. The levels of matrix metalloproteinase （MMP） 1， MMP2， MMP9 and tissue inhibitor of matrix metalloproteinase1 （TIMP1） were determined in the serum of rat by ELISA， and the pathologic changes of lung tissues were observed by HE staining and Masson staining. Results：①HE staining and Masson staining results showed that the degree of fibrosis in the astaxanthin group was significantly lower than that of the PQ group. ②The hydroxyproline content of model group was significantly higher than that of the normal group （P<0.05）. In the intervention of astaxanthin， the level of hydroxyproline in rat was decreased compared with the model group （P<0.05）. ③TGF-β1 was expressed in the PQ model group. After intervention of astaxanthin， the expression of TGF-β1 was decreased， especially at day 28， and the difference was statistically significant （P<0.05）. ④The expression levels of MMP1， MMP2 and MMP9 in the model group and the astaxanthin group were higher than those in the normal control group. The expressions of MMP1， MMP2， MMP9 after PQ poisoning were gradually increased， reached the highest point in day 14， then the expressions in day 14 began to decline but still higher than those of the control group. Compared with the model group， the contents of MMP9 and MMP2 in the astaxanthin group were decreased， and the difference was statistically significant （P<0.05） in the day 14 and day 28. TIMP1 had no significant difference between the model group and the control group during the intervention period （P>0.05）. Conclusion：Astaxanthin can reduce the content of hydroxyproline， MMP9， and MMP2， inhibit the secretion of TGF-β1 in lung tissue， and decrease the collagen deposition in lung tissue of rats with pulmonary fibrosis， further reduce PQ-induced pulmonary fibrosis in rats.
