TIMP-1 deficiency leads to lethal partial hepatic ischemia and reperfusion injury.
TIMP-1 deficiency leads to lethal partial hepatic ischemia and reperfusion injury.
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DOI：
10.1002/hep.25710
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发表时间：
2012-09
期刊：
影响因子：
13.5
通讯作者：
Coito, Ana J.
中科院分区：
文献类型：
--
作者：
Duarte, Sergio;Hamada, Takashi;Kuriyama, Naohisa;Busuttil, Ronald W.;Coito, Ana J.
肝缺血再灌注损伤（IRI）是临床原位肝移植（OLT）的一个重要挑战。组织金属蛋白酶-1抑制剂（TIMP-1）是基质金属蛋白酶-9 （MMP-9）的主要内源性调节因子。在这项研究中，我们研究了TIMP-1表达在建立的小鼠部分肝脏IRI模型中的功能意义。与野生型小鼠相比，TIMP-1−/−小鼠在IRI后肝脏功能和组织学保存进一步受损。值得注意的是，TIMP-1缺乏导致致命的肝脏IRI，因为超过60%的TIMP-1−/−小鼠在再灌注后死亡，而所有TIMP-1+/+小鼠都恢复并存活。TIMP-1表达的缺乏伴随着MMP-9活性的显著升高，这促进了肝脏IRI中白细胞跨越血管屏障的转运。事实上，TIMP-1−/−肝脏的特征是大量白细胞浸润，iri后促炎介质上调，包括TNF-α、IFN-γ和iNOS。TIMP-1−/−小鼠无法表达TIMP-1，可增加活性caspase-3水平，抑制Bcl-2表达和Akt磷酸化，强调TIMP-1表达在肝细胞存活中的重要作用。利用再生、5-溴脱氧尿苷（BrdU）掺入、增殖细胞核抗原（PCNA）表达和组蛋白H3磷酸化等独立参数，我们提供证据表明，IRI后，TIMP-1缺陷肝脏的肝细胞进展到S期和有丝分裂受到损害。TIMP-1缺乏对细胞周期进程的抑制与细胞周期蛋白- d1和-E水平的降低以及c-Met信号通路的破坏有关，这可以通过肝IRI后磷酸化c-Met表达减少和c-Met外结构域脱落升高来证明。总之，这些结果支持TIMP-1表达在肝脏IRI中促进肝细胞存活和增殖以及调节白细胞募集和激活的关键保护功能。
Hepatic ischemia and reperfusion injury (IRI) remains an important challenge in clinical orthotopic liver transplantation (OLT). Tissue inhibitor of metalloproteinase-1 (TIMP-1) is the major endogenous regulator of matrix metalloproteinase-9 (MMP-9). In this study, we investigated the functional significance of TIMP-1 expression in a well-established mouse model of partial liver IRI. Compared to wild-type mice, TIMP-1−/− mice showed further impaired liver function and histological preservation after IRI. Notably, TIMP-1 deficiency led to lethal liver IRI, as over 60% of the TIMP-1−/− mice died post-reperfusion, whereas all TIMP-1+/+ mice recovered and survived surgery. Lack of TIMP-1 expression was accompanied by markedly high levels of MMP-9 activity, which facilitates leukocyte transmigration across vascular barriers in hepatic IRI. Indeed, TIMP-1−/− livers were characterized by massive leukocyte infiltration and by upregulation of proinflammatory mediators, including TNF-α, IFN-γ, and iNOS, post-IRI. The inability of TIMP-1−/− mice to express TIMP-1 increased the levels of active caspase-3 and depressed the expression of Bcl-2 and the phosphorylation of Akt, emphasizing an important role for TIMP-1 expression on hepatocyte survival. Using independent parameters of regeneration, 5-bromodeoxyuridine (BrdU) incorporation, proliferating cell nuclear antigen (PCNA) expression, and histone H3 phosphorylation, we provide evidence that hepatocyte progression into S phase and mitosis was impaired in TIMP-1 deficient livers after IRI. Inhibition of the cell cycle progression by TIMP-1 deficiency was linked to depressed levels of cyclins-D1 and -E and to disrupted c-Met signaling pathway, as evidenced by reduced phosphorylated c-Met expression and elevated c-Met ectodomain shedding post-liver IRI. In conclusion, these results support a critical protective function for TIMP-1 expression on promoting survival and proliferation of liver cells and on regulating leukocyte recruitment and activation in liver IRI.
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