CX₃CL1/CX₃CR1 在大鼠实验性肝肺综合征肺血管生成和血管内单核细胞积累中的作用。
The role of CX₃CL1/CX₃CR1 in pulmonary angiogenesis and intravascular monocyte accumulation in rat experimental hepatopulmonary syndrome.
机构信息
Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, TX 77030-1501, United States.
出版信息
J Hepatol. 2012 Oct;57(4):752-8. doi: 10.1016/j.jhep.2012.05.014. Epub 2012 May 29.
BACKGROUND & AIMS: Hepatopulmonary syndrome (HPS), classically attributed to intrapulmonary vascular dilatation, occurs in 15-30% of cirrhotics and causes hypoxemia and increases mortality. In experimental HPS after common bile duct ligation (CBDL), monocytes adhere in the lung vasculature and produce vascular endothelial growth factor (VEGF)-A and angiogenesis ensues and contribute to abnormal gas exchange. However, the mechanisms for these events are unknown. The chemokine fractalkine (CX(3)CL1) can directly mediate monocyte adhesion and activate VEGF-A and angiogenesis via its receptor CX(3)CR1 on monocytes and endothelium during inflammatory angiogenesis. We explored whether pulmonary CX(3)CL1/CX(3)CR1 alterations occur after CBDL and influence pulmonary angiogenesis and HPS.
METHODS
Pulmonary CX(3)CL1/CX(3)CR1 expression and localization, CX(3)CL1 signaling pathway activation, monocyte accumulation, and development of angiogenesis and HPS were assessed in 2- and 4-week CBDL animals. The effects of a neutralizing antibody to CX(3)CR1 (anti-CX(3)CR1 Ab) on HPS after CBDL were evaluated.
RESULTS
Circulating CX(3)CL1 levels and lung expression of CX(3)CL1 and CX(3)CR1 in intravascular monocytes and microvascular endothelium increased in 2- and 4-week CBDL animals as HPS developed. These events were accompanied by pulmonary angiogenesis, monocyte accumulation, activation of CX(3)CL1 mediated signaling pathways (Akt, ERK) and increased VEGF-A expression and signaling. Anti-CX(3)CR1 Ab treatment reduced monocyte accumulation, decreased lung angiogenesis and improved HPS. These events were accompanied by inhibition of CX(3)CL1 signaling pathways and a reduction in VEGF-A expression and signaling.
CONCLUSIONS
Circulating CX(3)CL1 levels and pulmonary CX(3)CL1/CX(3)CR1 expression and signaling increase after CBDL and contribute to pulmonary intravascular monocyte accumulation, angiogenesis and development of experimental HPS.
背景与目的
肝肺综合征（HPS），经典归因于肺内血管扩张，发生在 15-30%的肝硬化患者中，导致低氧血症和增加死亡率。在胆总管结扎（CBDL）后的实验性 HPS 中，单核细胞在肺血管中黏附，并产生血管内皮生长因子（VEGF）-A 和随后的血管生成，导致异常气体交换。然而，这些事件的机制尚不清楚。趋化因子 fractalkine（CX（3）CL1）可以通过其在单核细胞和内皮细胞上的受体 CX（3）CR1 直接介导单核细胞黏附，并在炎症性血管生成过程中激活 VEGF-A 和血管生成。我们探讨了 CBDL 后肺部 CX（3）CL1/CX（3）CR1 是否发生改变，并影响肺部血管生成和 HPS。
方法
在 2 周和 4 周 CBDL 动物中评估肺部 CX（3）CL1/CX（3）CR1 表达和定位、CX（3）CL1 信号通路激活、单核细胞积累以及血管生成和 HPS 的发展。评估抗 CX（3）CR1 抗体（抗-CX（3）CR1 Ab）对 CBDL 后 HPS 的影响。
结果
随着 HPS 的发展，循环 CX（3）CL1 水平和血管内单核细胞和微血管内皮中肺表达的 CX（3）CL1 和 CX（3）CR1 在 2 周和 4 周 CBDL 动物中增加。这些事件伴随着肺部血管生成、单核细胞积累、CX（3）CL1 介导的信号通路（Akt、ERK）的激活以及 VEGF-A 表达和信号的增加。抗-CX（3）CR1 Ab 治疗减少单核细胞积累，减少肺血管生成，并改善 HPS。这些事件伴随着 CX（3）CL1 信号通路的抑制以及 VEGF-A 表达和信号的减少。
结论
CBDL 后循环 CX（3）CL1 水平和肺 CX（3）CL1/CX（3）CR1 表达和信号增加，并有助于肺内血管内单核细胞积累、血管生成和实验性 HPS 的发展。
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