Department of Biochemistry and Molecular Genetics, Hospital Clinic Universitari, Villarroel 170, Barcelona 08036, Spain.
Gut. 2013 Jan;62(1):138-45. doi: 10.1136/gutjnl-2011-300703. Epub 2012 Jan 20.
The lymphatic network plays a major role in maintaining tissue fluid homoeostasis. Therefore several pathological conditions associated with oedema formation result in deficient lymphatic function. However, the role of the lymphatic system in the pathogenesis of ascites and oedema formation in cirrhosis has not been fully clarified. The aim of this study was to investigate whether the inability of the lymphatic system to drain tissue exudate contributes to the oedema observed in cirrhosis.
Cirrhosis was induced in rats by CCl(4) inhalation. Lymphatic drainage was evaluated using fluorescent lymphangiography. Expression of endothelial nitric oxide synthase (eNOS) was measured in primary lymphatic endothelial cells (LyECs). Inhibition of eNOS activity in cirrhotic rats with ascites (CH) was carried out by L-N(G)-methyl-L-arginine (L-NMMA) treatment (0.5 mg/kg/day).
The (CH) rats had impaired lymphatic drainage in the splanchnic and peripheral regions compared with the control (CT) rats. LyECs isolated from the CH rats showed a significant increase in eNOS and nitric oxide (NO) production. In addition, the lymphatic vessels of the CH rats showed a significant reduction in smooth muscle cell (SMC) coverage compared with the CT rats. CH rats treated with L-NMMA for 7 days showed a significant improvement in lymphatic drainage and a significant reduction in ascites volume, which were associated with increased plasma volume. This beneficial effect of L-NMMA inhibition was also associated with a significant increase in lymphatic SMC coverage.
The upregulation of eNOS in the LyECs of CH rats causes long-term lymphatic remodelling, which is characterised by a loss of SMC lymphatic coverage. The amelioration of this lymphatic abnormality by chronic eNOS inhibition results in improved lymphatic drainage and reduced ascites.
淋巴系统在维持组织液动态平衡方面起着重要作用。因此，几种与水肿形成相关的病理状况导致淋巴功能不足。然而，淋巴系统在肝硬化腹水和水肿形成中的作用尚未完全阐明。本研究旨在探讨淋巴系统是否无法引流组织渗出物，导致肝硬化中观察到的水肿。
通过 CCl4 吸入诱导大鼠肝硬化。使用荧光淋巴管造影术评估淋巴引流。测量原代淋巴内皮细胞（LyECs）中内皮型一氧化氮合酶（eNOS）的表达。通过 L-N（G）-甲基-L-精氨酸（L-NMMA）处理（0.5mg/kg/天）抑制腹水（CH）肝硬化大鼠的 eNOS 活性。
与对照（CT）大鼠相比，（CH）大鼠的内脏和外周区域淋巴引流受损。从 CH 大鼠分离的 LyECs 显示 eNOS 和一氧化氮（NO）产生显著增加。此外，与 CT 大鼠相比，CH 大鼠的淋巴管平滑肌细胞（SMC）覆盖率显著降低。用 L-NMMA 治疗 7 天的 CH 大鼠，淋巴引流显著改善，腹水体积显著减少，血浆体积增加。这种 L-NMMA 抑制的有益作用还与淋巴管 SMC 覆盖率的显著增加有关。
CH 大鼠 LyECs 中 eNOS 的上调导致长期的淋巴重塑，其特征是 SMC 淋巴覆盖的丧失。通过慢性 eNOS 抑制改善这种淋巴异常可导致淋巴引流改善和腹水减少。
