Fibronectin-α4β1 interactions in hepatic cold ischemia and reperfusion injury: regulation of MMP-9 and MT1-MMP via the p38 MAPK pathway.
Fibronectin-α4β1 interactions in hepatic cold ischemia and reperfusion injury: regulation of MMP-9 and MT1-MMP via the p38 MAPK pathway.
复制标题
DOI：
10.1111/j.1600-6143.2012.04161.x
复制
发表时间：
2012-10
期刊：
影响因子：
--
通讯作者：
Coito AJ
中科院分区：
文献类型：
--
作者：
Duarte S;Shen XD;Fondevila C;Busuttil RW;Coito AJ
肝脏缺血再灌注损伤(IRI)在临床上仍是一个具有挑战性的问题。内皮细胞表达纤维连接蛋白(FN)是肝脏对损伤反应的一个显著特征。在这里，我们研究了连接片段-1(CS-1)肽治疗的效果，它阻断了纤维连接蛋白(FN)-α4β1整合素白细胞的相互作用，在一个公认的24小时冷肝缺血再灌注损伤模型中。CS-1多肽显著抑制白细胞募集和局部促炎介质(COX-2、iNOS、肿瘤坏死因子-α)的释放，改善肝脏缺血再灌注损伤，提高受体存活率。CS1治疗抑制了p38MAPK的磷酸化，p38MAPK是一种与炎症过程有关的激酶。此外，CS-1肽治疗除了下调肝脏IRI中基质金属蛋白酶-9(MMP9)的表达外，还可抑制巨噬细胞膜型基质金属蛋白酶(MT1-MMP1/MMP14)的表达，MMP1-MMP14是一种膜拴系的MMPs，对局灶性基质蛋白的降解起重要作用。用其药理拮抗剂SB203580抑制p38 MAPK活性可下调纤维连接蛋白刺激的巨噬细胞表达的MMP9和MT1-MMP14，提示P38MAPK信号通路控制纤维连接蛋白诱导的MMP9和MT1-MMP14的表达。因此，本研究对纤维连接蛋白在肝脏损伤中的作用提供了新的见解，可能被应用于开发成功预防肝脏IRI的新的药理策略。
Liver ischemia-reperfusion injury (IRI) remains a challenging problem in clinical settings. The expression of fibronectin (FN) by endothelial cells is a prominent feature of the hepatic response to injury. Here we investigate the effects of the connecting segment-1 (CS-1) peptide therapy, which blocks fibronectin (FN)-α4β1 integrin leukocyte interactions, in a well-established model of 24-hour cold liver IRI. CS-1 peptides significantly inhibited leukocyte recruitment and local release of proinflammatory mediators (COX-2, iNOS, and TNF-α), ameliorating liver IRI and improving recipient survival rate. CS1 therapy inhibited the phosphorylation of p38 MAPK, a kinase linked to inflammatory processes. Moreover, in addition to downregulating the expression of matrix metalloproteinase-9 (MMP-9) in hepatic IRI, CS-1 peptide therapy depressed the expression of membrane type 1-matrix metalloproteinase (MT1-MMP/MMP-14) by macrophages, a membrane-tethered MMP important for focal matrix proteolysis. Inhibition of p38 MAPK activity, with its pharmacological antagonist SB203580, downregulated MMP-9 and MT1-MMP/MMP-14 expressions by fibronectin-stimulated macrophages, suggesting that p38 MAPK kinase pathway controls fibronectin mediated inductions of MMP-9 and MT1-MMP/MMP-14. Hence, this study provides new insights on the role of fibronectin in liver injury, which can potentially be applied to the development of new pharmacological strategies for the successful protection against hepatic IRI.
登录
查看更多内容
DOI：
10.1007/s00534-009-0155-x
发表时间：
2009-11-01
期刊：
JOURNAL OF HEPATO-BILIARY-PANCREATIC SURGERY
影响因子：
--
作者：
King, LaShonda A.;Toledo, Alexander H.;Toledo-Pereyra, Luis H.
通讯作者：
Toledo-Pereyra, Luis H.
影响因子：
56.9
作者：
Johnson, GL;Lapadat, R
通讯作者：
Lapadat, R
影响因子：
4.4
作者：
Fiorino, Gionata;Correale, Carmen;Danese, Silvio
通讯作者：
Danese, Silvio
影响因子：
13.5
作者：
Fondevila, C;Shen, XD;Bach, FH
通讯作者：
Bach, FH
影响因子：
13.5
作者：
Le Moine, O;Louis, H;Devière, J
通讯作者：
Devière, J