1. Cyclooxygenase-2 promotes pulmonary intravascular macrophage accumulation by exacerbating BMP signaling in rat experimental hepatopulmonary syndrome.
- Author
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Liu C, Gao J, Chen B, Chen L, Belguise K, Yu W, Lu K, Wang X, and Yi B
- Subjects
- Animals, Bone Morphogenetic Protein 2 administration & dosage, Bone Morphogenetic Protein 2 genetics, Bone Morphogenetic Protein 2 therapeutic use, Carrier Proteins administration & dosage, Carrier Proteins genetics, Carrier Proteins metabolism, Carrier Proteins therapeutic use, Cells, Cultured, Cyclooxygenase 2 chemistry, Cyclooxygenase 2 Inhibitors administration & dosage, Cyclooxygenase 2 Inhibitors therapeutic use, Endothelium, Vascular drug effects, Endothelium, Vascular immunology, Endothelium, Vascular metabolism, Endothelium, Vascular pathology, Hepatopulmonary Syndrome drug therapy, Hepatopulmonary Syndrome immunology, Hepatopulmonary Syndrome pathology, Injections, Intraperitoneal, Injections, Intravenous, Isoxazoles administration & dosage, Isoxazoles therapeutic use, Lung drug effects, Lung immunology, Lung pathology, Macrophages, Alveolar drug effects, Macrophages, Alveolar immunology, Macrophages, Alveolar metabolism, Macrophages, Alveolar pathology, Microvessels drug effects, Microvessels immunology, Microvessels metabolism, Microvessels pathology, Neovascularization, Pathologic physiopathology, Neovascularization, Pathologic prevention & control, Rats, Sprague-Dawley, Recombinant Proteins administration & dosage, Recombinant Proteins metabolism, Recombinant Proteins therapeutic use, Bone Morphogenetic Protein 2 metabolism, Cyclooxygenase 2 metabolism, Disease Models, Animal, Hepatopulmonary Syndrome metabolism, Lung metabolism, Macrophage Activation drug effects, Signal Transduction drug effects
- Abstract
Background and Aims: One central factor in hepatopulmonary syndrome (HPS) pathogenesis is intravascular accumulation of activated macrophages in small pulmonary arteries. However, molecular mechanism underlying the macrophage accumulation in HPS is unknown. In this study, we aimed to explore whether elevated COX-2 induces the Bone morphogenic protein-2 (BMP-2)/Crossveinless-2 (CV-2) imbalance and then activation of BMP signaling pathway promotes the macrophage accumulation in Common Bile Duct Ligation (CBDL) rat lung., Methods: The COX-2/PGE2 signaling activation, the BMP-2/CV-2 imbalance and the activation of Smad1 were evaluated in CBDL rat lung and in cultured pulmonary microvascular endothelial cells (PMVECs) under the HPS serum stimulation. The effects of Parecoxib (COX-2 inhibitor), BMP-2 and CV-2 recombinant proteins on 4-week CBDL rat lung were determined, respectively., Results: The COX-2/PGE2 signaling pathway was activated in CBDL rat lung in vivo and PMVECs in vitro, which was due to the activation of NF-κB P65. The inhibition of COX-2 by Parecoxib reduced macrophage accumulation, decreased lung angiogenesis and improved HPS. Meanwhile, the CBDL rat lung secreted more BMP-2 but less CV-2, and the imbalance between BMP-2 and CV-2 exacerbated the BMP signaling activation thus promoting the macrophage accumulation and lung angiogenesis. The BMP-2/CV-2 imbalance is dependent on the COX-2/PGE2 signaling pathway, and thus the effects of this imbalance can be reversed by adminstration of Parecoxib., Conclusion: Our findings indicate that inhibition of COX-2 by parecoxib can improve the HPS through the repression of BMP signaling and macrophage accumulation., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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