F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells:: a link with liver fibrosis?
F2-isoprostanes stimulate collagen synthesis in activated hepatic stellate cells:: a link with liver fibrosis?
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DOI：
10.1038/labinvest.3700332
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发表时间：
2005-11-01
影响因子：
5
通讯作者：
Gardi, C
中科院分区：
文献类型：
--
作者：
Comporti, M;Arezzini, B;Gardi, C
四氯化碳（CCl4）诱导的肝纤维化被认为与氧化应激有关，并由醛类脂质过氧化产物介导。在本研究中，我们研究了胶原合成是否由f -2异前列腺素诱导，f -2异前列腺素是脂质过氧化最接近的产物，也是已知的重要生物效应介质。与醛相比，f -2-异前列腺素通过能够引发明确信号转导途径的受体起作用。在ccl4诱导的肝纤维化大鼠模型中，血浆f -2-异前列腺素在整个实验期间显著升高；肝胶原蛋白含量也有所增加。当正常肝脏的肝星状细胞（hsc）与体内研究中发现的浓度范围(10（-9)- 10(-8)M）的f -2异前列腺素一起培养时，观察到DNA合成（被血栓素a(2)拮抗剂SQ 29548逆转）、细胞增殖和胶原合成的显著增加。总胶原蛋白含量也同样增加。此外，f -2-异前列腺素显著增加了被认为是肝巨噬细胞模型的U937细胞产生转化生长因子- β 1。这些数据为肝细胞脂质过氧化产生的f -2异前列腺素介导肝纤维化中可见的HSC增殖和胶原生成的可能性提供了证据。
Carbon tetrachloride (CCl4)-induced hepatic fibrosis has been considered to be linked to oxidative stress and mediated by aldehydic lipid peroxidation products. In the present study, we investigated whether collagen synthesis is induced by F-2-isoprostanes, the most proximal products of lipid peroxidation and known mediators of important biological effects. By contrast with aldehydes, F-2-isoprostanes act through receptors able to elicit definite signal transduction pathways. In a rat model of CCl4-induced hepatic fibrosis, plasma F-2-isoprostanes were markedly elevated for the entire experimental period; hepatic collagen content also increased. When hepatic stellate cells (HSCs) from normal liver were cultured with F-2-isoprostanes in the concentration range found in the in vivo studies (10(-9) - 10(-8) M), a striking increase in DNA synthesis ( reversed by the thromboxane A(2) antagonist SQ 29 548), in cell proliferation and in collagen synthesis was observed. Total collagen content was similarly increased. Moreover, F-2-isoprostanes markedly increased the production of transforming growth factor-beta 1 by U937 cells, considered a model of liver macrophages. The data provide evidence for the possibility that F-2-isoprostanes generated by lipid peroxidation in hepatocytes mediate HSC proliferation and collagen production seen in hepatic fibrosis.