Research Article| Volume 57, ISSUE 4, P752-758, October 2012

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The role of CX3CL1/CX3CR1 in pulmonary angiogenesis and intravascular monocyte accumulation in rat experimental hepatopulmonary syndrome

  • Junlan Zhang
    Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, TX, United States
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  • Wenli Yang
    Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, TX, United States
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  • Bao Luo
    Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, TX, United States
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  • Bingqian Hu
    Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, TX, United States
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  • Akhil Maheshwari
    Division of Neonatology, University of Illinois at Chicago, IL, United States
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  • Michael B. Fallon
    Corresponding author. Address: The University of Texas Health Science Center at Houston, UT Medical School Houston, Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, 6431 Fannin Street, MSB 4.234, Houston, TX 77030-1501. Tel.: +1 713 500 6677; fax: +1 713 500 6699.
    Department of Internal Medicine, Division of Gastroenterology, Hepatology and Nutrition, The University of Texas Health Science Center at Houston, TX, United States
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      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 (CX3CL1) can directly mediate monocyte adhesion and activate VEGF-A and angiogenesis via its receptor CX3CR1 on monocytes and endothelium during inflammatory angiogenesis. We explored whether pulmonary CX3CL1/CX3CR1 alterations occur after CBDL and influence pulmonary angiogenesis and HPS.


      Pulmonary CX3CL1/CX3CR1 expression and localization, CX3CL1 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 CX3CR1 (anti-CX3CR1 Ab) on HPS after CBDL were evaluated.


      Circulating CX3CL1 levels and lung expression of CX3CL1 and CX3CR1 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 CX3CL1 mediated signaling pathways (Akt, ERK) and increased VEGF-A expression and signaling. Anti-CX3CR1 Ab treatment reduced monocyte accumulation, decreased lung angiogenesis and improved HPS. These events were accompanied by inhibition of CX3CL1 signaling pathways and a reduction in VEGF-A expression and signaling.


      Circulating CX3CL1 levels and pulmonary CX3CL1/CX3CR1 expression and signaling increase after CBDL and contribute to pulmonary intravascular monocyte accumulation, angiogenesis and development of experimental HPS.


      HPS (hepatopulmonary syndrome), CBDL (common bile duct ligation), VEGF (vascular endothelial growth factor), eNOS (endothelial nitric oxide synthase), MCP-1 (monocyte chemotactic protein-1), MIP-1α (macrophage inflammatory protein-1 alpha), SDF-1α (stromal derived factor-1 alpha), RANTES (regulated upon activation, normal T cell expressed and secreted), anti-CX3CR1 Ab (anti-CX3CR1-neutralizing antibody), ERK (extracellular signal-regulated kinase), FVIII (factor VIII), vWf (von Willebrand factor), MEK (mitogen-activated protein kinase kinase), p-Akt (phospho-Akt), PCNA (proliferating cell nuclear antigen), p-VEGFR-2 (phospho-vascular endothelial growth factor receptor-2)


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