Role of Matrix Metalloproteinase-2 in Liver Fibrosis

描述（由申请人提供）： 无论慢性肝损伤的病因如何，肝损伤和肝衰竭的最终共同途径是纤维化。肝纤维化伴门静脉高压并发症可导致等待肝移植的患者死亡。鉴于供体器官的严重短缺，迫切需要了解肝纤维化的分子基础，以制定有效的抗纤维化策略。肝纤维化的特征在于肝星状细胞的活化，其协调主要由IV型胶原组成的正常细胞外（ECM）向主要由I型胶原组成的高密度间质基质的转变。因此，潜在的抗纤维化策略包括减少I型胶原合成、刺激基质降解和/或促进星状细胞凋亡。基质金属蛋白酶-2（MMP-2），一种由活化的肝星状细胞（HSC）产生的IV型胶原酶，在慢性肝炎和肝硬化患者中增加，表明在纤维化过程中起致病作用。MMP-2也能够作为I型胶原酶，在动物和人肝纤维化中上调，在纤维化消退期间增加，并且与星状细胞凋亡相关，我们假设MMP-2在慢性肝损伤中可能起保护作用而不是有害作用。MMP-2 -/-小鼠为阐明MMP-2在肝纤维化中的生理作用提供了机会。本研究将使用四氯化碳诱导的慢性肝损伤模型来确定MMP-2是否通过直接减少I型胶原表达而在减轻肝纤维化中起重要作用。其在充当间质胶原酶中的作用将通过1）比较MMP-2 -/-和MMP-2 +/+小鼠之间纤维化的自发消退速率和2）定量两个队列中的间质胶原酶活性来评估。此外，MMP-2在促进星状细胞凋亡中的潜在作用将在体内和体外模型中进行研究。这些研究的结果可能会导致慢性纤维化肝病治疗的新方法。

DESCRIPTION (provided by applicant): Regardless of the etiology of chronic liver injury, the final common pathway for liver injury and failure is fibrosis. Fibrosis with subsequent complications of portal hypertension results in the death of patients awaiting liver transplantation. Given the severe shortage of donor organs, there is an urgent need to understand the molecular basis of hepatic fibrosis in order to develop effective anti-fibrotic strategies. Liver fibrosis is characterized by activation of hepatic stellate cells which orchestrate a shift in the normal extracellular (ECM) comprised of mostly collagen type IV to a high-density interstitial matrix composed of predominantly type I collagen. Therefore, potential antifibrotic strategies include reduction in type I collagen synthesis, stimulation of matrix degradation, and/or promotion of stellate cell apoptosis. Matrix metalloproteinase-2 (MMP-2), a type IV collagenase, produced by activated hepatic stellate cells (HSCs), is increased in patients with chronic hepatitis and cirrhosis, suggesting a causative role in the fibrotic process. MMP-2 is also capable of acting as a type I collagenase, is upregulated in both animal and human hepatic fibrosis, is increased during resolution of fibrosis, and is associated with stellate cell apoptosis, we hypothesize that MMP-2 may play a protective rather than deleterious role in chronic liver injury. MMP-2 -/- mice offer an opportunity to clarify the physiologic role of MMP-2 in liver fibrosis. This study will employ the use of CCI4-induced chronic liver injury model to determine whether MMP-2 is important in attenuating liver fibrosis by directly reducing collagen I expression. Its role in acting as an interstitial collagenase will be assessed by 1) comparing the rate of spontaneous resolution of fibrosis between MMP-2 -/- and MMP-2 +/+ mice and 2) quantifying interstitial collagenase activity in both cohorts. In addition, a potential role for MMP-2 in promoting stellate cell apoptosis will be examined in both in vivo and in vitro models. Findings from these investigations may lead to novel approaches to the treatment of chronic fibrosing liver disease.