Department of Pharmacology, Instituto Nacional Cardiología Ignacio Chávez, Mexico City, Distrito Federal, Mexico.
Liver Transpl. 2011 Mar;17(3):334-43. doi: 10.1002/lt.22238.
Although increased plasma enzyme activities could be diagnostic for tissue damage, the mechanisms controlling cellular enzyme release remain poorly understood. We found a selective and drastic elevation of serum enzyme activities accompanying rat liver regeneration after partial hepatectomy (PH), apparently controlled by a mechanism dependent on flow-bearing physical forces. In fact, this study assesses a putative role of calcium mobilization and nitric oxide (NO) production underlying rat liver enzyme release. The role of increased shear stress (by enhancing viscosity during perfusion) and the participation of cell calcium and NO were tested in isolated livers subjected to increasing flow rate. After PH, there was a drastic elevation of serum activities for liver enzyme markers, clearly predominating those of mitochondrial localization. Liver enzyme release largely depended on extracellular calcium entry, probably mediated by stretch-sensitive calcium channels, as well as by increasing NO production. However, these effects were differentially observed when comparing liver enzymes from cytoplasmic or mitochondrial compartments. Moreover, a possible role for cell-mediated mechanotransduction in liver enzyme release was suggested by increasing shear stress (high viscosity), which also selectively affected the release of the enzymes tested. Therefore, we show, for the first time, that flow-induced shear stress can control the amount of hepatic enzymes released into the bloodstream, which is largely regulated through modifications in cell calcium mobilization and production of liver NO, events markedly elevated in the proliferating rat liver.
尽管血浆酶活性的增加可能是组织损伤的诊断指标，但控制细胞酶释放的机制仍知之甚少。我们发现，在大鼠肝部分切除（PH）后，伴随着肝再生，血清酶活性明显升高，显然是由一种依赖于承载血流的物理力的机制控制的。事实上，本研究评估了钙动员和一氧化氮（NO）产生在大鼠肝酶释放中的潜在作用。在分离的肝脏中，通过增加灌注时的粘度来增加切变应力（shear stress）以及细胞钙和 NO 的参与，来检测增加的流动速率。在 PH 后，血清中肝酶标志物的活性明显升高，明显占优势的是线粒体定位的酶。肝酶的释放主要取决于细胞外钙内流，可能是由伸展敏感钙通道介导的，同时也增加了 NO 的产生。然而，当比较细胞质或线粒体区室中的肝酶时，观察到这些作用存在差异。此外，通过增加剪切应力（高粘度），可以提示细胞介导的机械转导在肝酶释放中的可能作用，剪切应力也选择性地影响了所测试的酶的释放。因此，我们首次表明，流动诱导的切变应力可以控制释放到血液中的肝酶的量，这主要是通过细胞钙动员的改变和肝 NO 的产生来调节的，这些事件在增殖的大鼠肝中明显升高。
