TY - JOUR
T1 - The role of CX3CL1/CX3CR1 in pulmonary angiogenesis and intravascular monocyte accumulation in rat experimental hepatopulmonary syndrome
AU - Zhang, Junlan
AU - Yang, Wenli
AU - Luo, Bao
AU - Hu, Bingqian
AU - Maheshwari, Akhil
AU - Fallon, Michael B.
N1 - Funding Information:
Supported by 5DKR01DK056804 to M.B.F, a Scientist Development Award (AHA) and a Pilot/Feasibility project (The Texas Medical Center Digestive Diseases Center) to J.Z, and 5R01HD059142 to A.M.
Funding Information:
The underlying research reported in the study was funded by the NIH Institutes of Health.
PY - 2012/10
Y1 - 2012/10
N2 - 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 CX 3CR1 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-CX 3CR1 Ab) on HPS after CBDL were evaluated. Results: Circulating CX3CL1 levels and lung expression of CX3CL1 and CX 3CR1 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 CX 3CL1 levels and pulmonary CX3CL1/CX3CR1 expression and signaling increase after CBDL and contribute to pulmonary intravascular monocyte accumulation, angiogenesis and development of experimental HPS.
AB - 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 CX 3CR1 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-CX 3CR1 Ab) on HPS after CBDL were evaluated. Results: Circulating CX3CL1 levels and lung expression of CX3CL1 and CX 3CR1 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 CX 3CL1 levels and pulmonary CX3CL1/CX3CR1 expression and signaling increase after CBDL and contribute to pulmonary intravascular monocyte accumulation, angiogenesis and development of experimental HPS.
KW - Angiogenesis
KW - Common bile duct ligation
KW - Fractalkine
KW - Hepatopulmonary syndrome
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U2 - 10.1016/j.jhep.2012.05.014
DO - 10.1016/j.jhep.2012.05.014
M3 - Article
C2 - 22659346
AN - SCOPUS:84866402456
SN - 0168-8278
VL - 57
SP - 752
EP - 758
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 4
ER -