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.
Methods
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.
Results
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.
Conclusions
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.
Abbreviations:
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)Keywords
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References
- Hepatopulmonary syndrome – a liver-induced lung vascular disorder.N Engl J Med. 2008; 358: 2378-2387
- Impact of hepatopulmonary syndrome on quality of life and survival in liver transplant candidates.Gastroenterology. 2008; 135: 1168-1175
- Prognostic significance of the hepatopulmonary syndrome in patients with cirrhosis.Gastroenterology. 2003; 125: 1042-1052
- Natural history of hepatopulmonary syndrome: impact of liver transplantation.Hepatology. 2005; 41: 1122-1129
- Pulmonary angiogenesis in a rat model of hepatopulmonary syndrome.Gastroenterology. 2009; 136: 1070-1080
- A central role for cd68(+) macrophages in hepatopulmonary syndrome: Reversal by macrophage depletion.Am J Respir Crit Care Med. 2011; 183: 1080-1091
- Chemokine receptor cx3cr1 mediates skin wound healing by promoting macrophage and fibroblast accumulation and function.J Immunol. 2008; 180: 569-579
- Macrophages and their products in rheumatoid arthritis.Curr Opin Rheumatol. 2007; 19: 289-295
- Tie2-expressing monocytes: regulation of tumor angiogenesis and therapeutic implications.Trends Immunol. 2007; 28: 545-550
- Myeloid cell trafficking and tumor angiogenesis.Cancer Lett. 2007; 250: 1-8
- Chemokines in cutaneous wound healing.J Leukoc Biol. 2001; 69: 513-521
- Fractalkine stimulates angiogenesis by activating the raf-1/mek/erk- and pi3k/akt/enos-dependent signal pathways.Am J Physiol Heart Circ Physiol. 2006; 291: H2836-2846
- Platelets and stromal cell-derived factor-1 in progenitor cell recruitment.Semin Thromb Hemost. 2007; 1: 159-164
- Up-regulated expression of fractalkine and its receptor cx3cr1 during liver injury in humans.J Hepatol. 2002; 37: 39-47
- Fractalkine and cx3cr1 are involved in the recruitment of intraepithelial lymphocytes of intrahepatic bile ducts.Hepatology. 2005; 41: 506-516
- Identification and molecular characterization of fractalkine receptor cx3cr1, which mediates both leukocyte migration and adhesion.Cell. 1997; 91: 521-530
- Activation of fractalkine/cx3cr1 by vascular endothelial cells induces angiogenesis through vegf-a/kdr and reverses hindlimb ischaemia.Cardiovasc Res. 2008; 78: 333-340
- Common bile duct ligation in the rat: a model of intrapulmonary vasodilatation and hepatopulmonary syndrome.Am J Physiol. 1997; 272: G779-G784
- Altered organ levels of vasoactive mediators in cirrhotic and non-cirrhotic rat models of portal hypertension.Gastroenterology. 1997; 112: A1262
- The role of endothelial nitric oxide synthase in the pathogenesis of a rat model of hepatopulmonary syndrome.Gastroenterology. 1997; 113: 606-614
- Modulation of pulmonary endothelial endothelin b receptor expression and signaling: implications for experimental hepatopulmonary syndrome.Am J Physiol Lung Cell Mol Physiol. 2007; 292: L1467-1472
- Analysis of pulmonary heme oxygenase-1 and nitric oxide synthase alterations in experimental hepatopulmonary syndrome.Gastroenterology. 2003; 125: 1441-1451
- Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells.Cancer Res. 2004; 64: 5311-5321
- Mcp-1/ccl2 as a therapeutic target in myocardial infarction and ischemic cardiomyopathy.Inflamm Allergy Drug Targets. 2007; 6: 101-107
- Pulmonary dysfunction in non-cirrhotic patients with chronic viral hepatitis.Eur J Intern Med. 2002; 13: 311-318
- Prevalence of hepatopulmonary syndrome in cirrhosis and extrahepatic portal venous obstruction.Am J Gastroenterol. 2001; 96: 3395-3399
- Transient hepatopulmonary syndrome in a patient with acute hepatitis a.J Viral Hep. 2001; 8: 83-86
- Pulmonary-hepatic vascular disorders (phd).Eur Respir J. 2004; 24: 861-880
- Characterization of time-related changes after experimental bile duct ligation.Br J Surg. 2008; 95: 646-656
- Microsurgical extrahepatic cholestasis in the rat: A long-term study.J Invest Surg. 2004; 17: 99-104
- A method to prevent recanalization of the transected bile duct in the rat.Scand J Gastroenterol. 1985; 20: 428-432
- The effects of ligation of the common bile duct in the rat.J Anat. 1964; 98: 227-233
- Fractalkine, a novel chemokine in rheumatoid arthritis and in rat adjuvant-induced arthritis.Arthritis Rheum. 2001; 44: 1568-1581
- Fractalkine: a novel angiogenic chemokine in rheumatoid arthritis.Am J Pathol. 2001; 159: 1521-1530
- Small airway obstruction in severe pulmonary arterial hypertension correlates with increased airway cd8+ t-cells and fractalkine expression.Eur Respir J. 2009; 34: 1494-1496
- Cx3cl1 up-regulation is associated with recruitment of cx3cr1+ mononuclear phagocytes and t lymphocytes in the lungs during cigarette smoke-induced emphysema.Am J Pathol. 2008; 173: 949-961
- Regulation of cx3cl1/fractalkine expression in endothelial cells.J Atheroscler Thromb. 2004; 11: 15-21
- C and cx3c chemokines: cell sources and physiopathological implications.Crit Rev Immunol. 2004; 24: 205-228
- Map kinases, phosphatidylinositol 3-kinase, and p70 s6 kinase mediate the mitogenic response of human endothelial cells to vascular endothelial growth factor.J Cell Physiol. 1999; 178: 235-246
- Vascular endothelial growth factor regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/akt signal transduction pathway. Requirement for flk-1/kdr activation.J Biol Chem. 1998; 273: 30336-30343
- Vegf prevents apoptosis of human microvascular endothelial cells via opposing effects on mapk/erk and sapk/jnk signaling.Exp Cell Res. 1999; 247: 495-504
- The vascular endothelial growth factor receptor kdr activates multiple signal transduction pathways in porcine aortic endothelial cells.J Biol Chem. 1997; 272: 32521-32527
- Signaling angiogenesis via p42/p44 map kinase and hypoxia.Biochem Pharmacol. 2000; 60: 1171-1178
- Role for extracellular signal-responsive kinase-1 and -2 in retinal angiogenesis.Invest Ophthalmol Vis Sci. 2003; 44: 1722-1731
- Phosphatidylinositol 3-kinase signaling mediates angiogenesis and expression of vascular endothelial growth factor in endothelial cells.Proc Natl Acad Sci USA. 2000; 97: 1749-1753
- Carboxyhemoglobin levels in cirrhotic patients with and without hepatopulmonary syndrome.Gastroenterology. 2005; 128: 328-333
Article info
Publication history
Published online: May 30, 2012
Accepted:
May 17,
2012
Received in revised form:
May 14,
2012
Received:
July 21,
2011
Identification
Copyright
© 2012 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved.
