灯盏花素对低氧诱导的大鼠肺泡炎症及细胞外基质沉积的作用
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四川省科技厅攻关项目(0040205301469)


Effect of Breviscapine on hypoxiainduced inflammation and ECM deposition in SD Rats’ lung
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    【摘要】 目的 观察间歇性常压性低氧对大鼠肺组织中TGFβ1、Smad4蛋白、Col I、TNFα表达量的影响及灯盏花素对其的干预作用。方法 将80只SPF级SD大鼠随机分为对照组、单纯低氧组、低氧+低剂量灯盏花素组,低氧+高剂量灯盏花素组,分别置于常氧或间歇性常压性低氧(101kPa,10% O2,每天低氧8h)条件下,于3、7、14、21d每组随机处死5只大鼠。HE染色观察肺组织病理改变;免疫组化染色检测肺组织TGFβ1、Col I表达;Westernblot法检测Smad4通道蛋白的表达;RTPCR检测TGFβ1、Col I的mRNA表达量;ELISA法检测肺泡灌洗液(BALF)中TNFα的表达。结果 HE染色结果显示低氧可引起大鼠肺组织水肿及炎症细胞浸润,且随低氧时间延长,炎症反应加重,肺泡间隔逐渐增厚,而药物干预组水肿、炎症反应及间隔增厚程度均较单纯低氧组轻;单纯低氧组大鼠肺组织中TGFβ1、Smad4、Col I蛋白及TGFβ1 mRNA、Col I mRNA表达量均较对照组增高(P<001),随低氧时间延长,各因子表达量逐渐增高,且Smad4蛋白表达水平与TGFβ1表达水平呈正相关(r=0944,P<001),BALF中TNFα的表达上调(P<001)。药物干预组TGFβ1、Smad4、Col I及TNFα蛋白、Col I mRNA的表达量均较单纯低氧组下调(P<005),且低氧+高剂量灯盏花素组较低氧+低剂量灯盏花素组降低(P<005),但TGFβ1mRNA的表达量单纯低氧、低氧+低剂量灯盏花素、低氧+高剂量灯盏花素三组比较差异无统计学意义(P>005)。结论 低氧可能通过诱发肺泡水肿及炎症反应,上调TNFα水平、激活TGFβ1/Smads通路从而增加Col I合成,引发细胞外基质沉积;灯盏花素则通过调节TGFβ1及Smad4蛋白表达,下调Col ImRNA及蛋白表达,并降低TNFα水平,抑制低氧诱导的肺组织结构改变。

    Abstract:

    【Abstract】 Objective To observe the effect of intermittent normobaric hypoxia on the expression of Transforming Growth Factor beta1 (TGFβ1), Smad4, collagen I(Col I), Tumor Necrosis Factor alpha(TNFα) and on the changes in the histological structure of the Rats’ Lung and the effect of breviscapine on the hypoxiainduced changes. Methods 80 Rats were randomly divided into control group (group A), hypoxia group (group B), hypoxia and lowdose breviscapine group (group C), hypoxia and highdose breviscapine group (group D). They were placed in normal environment or intermittent normobaric hypoxia (101kpa,10% O2, 8h every day), respectively. At the 3d, 7th, 14th, 21st day, 5 rats from each group were killed, Hematoxylin and Eosin staining (HE staining) was taken to observe the pathological change in the rats’ lung, Immunohistochemical staining to detect the protein level of TGFβ1, Col I and Western blot to detect the expression of Smad4. RTPCR was performed to detect the mRNA levels of TGFβ1 and Col I. Besides, the TNFαin the bronchoalveolar lavage fluid (BALF) were determined by ELISA. Results HE staining shown that mild edema and inflammatory cell infiltration appear in the lung tissue at the 3d day, meanwhile inflammation gradually aggravated, and the interalveolar septum became thicker and thicker as the time of exposing to hypoxia going on. In both breviscapine groups, the degree of hypoxiainduced inflammation and the septum changes were lighter than that in the hypoxia group. Compared with the normoxia group, not only the protein expression of TGFβ1, Smad4,Col I and TNFα, but also the mRNA expression of TGFβ1and Col I were elevated, and with longer exposure to hypoxia they increase further. It also demonstrated positive correlation between the protein level of TGFβ1 and Smad4. Meanwhile the protein of TGFβ1, Smad4, Col I, TNFα and Col I mRNA detected in both the breviscapine groups were declined. The expression level in group D was lower than group C. There is no statistical difference in TGFβ1mRNA in the three groups, B,C and D. Conclusion Via inducing pulmonary edema and inflammation, upregulating expression of TNFαand activating the TGFβ1/Smads Signaling Pathway, hypoxia induces the synthesization of Col I increase, extracellular matrix deposite and interalveolar septum thicken. While breviscapine maybe can inhibit the TGFβ1/Smads Signaling Pathway, decrease the expression of TNFαand Col I and protect the lung from tissue remodeling.

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  • 在线发布日期: 2018-08-01
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