Fibrolytic Activation of Hepatic Stellate Cells by T Cell Derived Microparticles

描述（由申请人提供）：慢性肝病患者经常进展为纤维化，最终为肝硬化。肝硬化是肝脏相关死亡率的最重要决定因素。目前，还没有经过证实的治疗方法来阻止纤维化进展或逆转肝硬化。激活的肝星状细胞和肌成纤维细胞（统称为HSC）在肝纤维化中产生大部分瘢痕组织，从而驱动纤维形成。在早期活化过程中，相同的细胞也表达溶解瘢痕成分的酶，例如某些基质金属蛋白酶（MMP）。虽然HSC的纤维化激活是相当明确的，但它们溶解瘢痕组织的潜力，即，以诱导纤维溶解，在很大程度上是未探索的。我们已经证明：1）来自凋亡或活化的T细胞而不是来自肝细胞的细胞膜衍生的微粒（MP）诱导HSC中纤维溶解性MMPs的表达; 2）这些MP与HSC细胞膜融合; 3）纤维溶解性基因的表达通过Erk 1/2、核因子κ B（NF κ B）和p38激酶1的活化而触发;和4）MP含有可能是HSC纤维溶解活化的候选者的膜分子。该提议的中心假设是，从T细胞释放的MP可以诱导HSC中的纤维溶解表型，从而潜在地逆转肝纤维化和肝硬化。我们的目标是：1）鉴定产生最有效的纤维溶解MP的T细胞亚群，和2）鉴定MP诱导纤维溶解基因的分子和信号转导途径。目的1研究活化T细胞亚群释放的MP对HSC纤维化/纤维溶解表型的影响。T细胞将是CD 4+、CD 8+、CD 25+和Th 1或Th 2 T极化的。目的2将确定的分子和检查的信号转导途径，导致收购的HSC暴露于MP的纤维溶解表型。我们提出的研究将提供有关MP对HSC纤维溶解活化的贡献以及它们在纤维化肝脏的有利结构重塑中的潜在作用的信息。所获得的信息也将影响对以慢性炎症为共同特征的其他器官病理中纤维溶解的理解。我们的长期目标是探索基于MP的治疗晚期肝纤维化的新策略。

DESCRIPTION (provided by applicant): Patients with chronic liver disease frequently progress to fibrosis and finally cirrhosis. Cirrhosis is the most important determinant of liver-related mortality. At present there exists no proven therapy to halt fibrosis progression or to reverse cirrhosis. Activated hepatic stellate cells and myofibroblasts (collectively termed HSC) produce most of the scar tissue in liver fibrosis and thus drive fibrogenesis. During early activation the same cells also express the enzymes that dissolve scar components, such as certain matrix metalloproteinases (MMPs). While fibrogenic activation of HSC is fairly well defined, their potential to dissolve scar tissue, i.e., to induce fibrolysis, is largely unexplored. We have shown that 1) cell membrane derived microparticles (MP) from apoptotic or activated T cells but not from hepatocytes induce the expression of fibrolytic MMPs in HSC; 2) these MP fuse with HSC cell membranes; 3) fibrolytic gene expression is triggered via activation of Erk1/2, nuclear factor kappa B (NFkB) and p38 kinase l; and 4) MP contain membrane molecules that are likely candidates of HSC fibrolytic activation. The central hypothesis of this proposal is that MP released from T-cells can induce a fibrolytic phenotype in HSC, potentially reversing liver fibrosis and cirrhosis. Our goals are 1) to identify T cell subsets that generate the most effective fibrolytic MP, and 2) to identify the molecules and signal transduction pathways by which MP induce fibrolytic genes. Aim 1 will study the effect of MP released from activated T-cell subpopulations on the fibrogenic/fibrolytic phenotype of HSC. T cells will be CD4+, CD8+, CD25+, and Th1 or Th2 T- polarized. Aim 2 will identify the molecules and examine the signal transduction pathways that lead to acquisition of a fibrolytic phenotype by HSC exposed to MP. Our proposed studies will provide information on the contribution of MP to fibrolytic activation of HSC, and their potential role in favorable architectural remodeling of the fibrotic liver. The information gained will also impact on the understanding of fibrolysis in other organ pathologies which have chronic inflammation as a common feature. Our long-term goal is to explore novel MP-based strategies to treat advanced hepatic fibrosis.