Huiying Zhang1, Minli Lv2, Zhongfu Zhao3, Jiantao Jia4, Lili Zhang4, Peng Xiao5, Limin Wang6, Chen Li7, Jingquan Ji4, Xiaoxia Tian4, Xujiong Li7, Yimin Fan6, Lina Lai8, Yan Liu7, Baohong Li4, Cuiying Zhang6, Mingshe Liu3, Jianhong Guo9, Dewu Han9, Cheng Ji10. 1. Pathophysiology Department of Changzhi Medical College, Shanxi 046000, PR China. Electronic address: zhanghy2001@163.com. 2. ICU of the Second Hospital of Shanxi Medical University, Shanxi 030001, PR China. 3. Institute of Hepatology of Changzhi Medical College, Shanxi 046000, PR China. 4. Pathophysiology Department of Changzhi Medical College, Shanxi 046000, PR China. 5. Pathology Department of Changzhi Medical College, Shanxi 046000, PR China. 6. Functional Laboratory of Changzhi Medical College, Shanxi 046000, PR China. 7. Physiology Department of Changzhi Medical College, Shanxi 046000, PR China. 8. Pharmacology Department of Changzhi Medical College, Shanxi 046000, PR China. 9. Institute of Hepatology of Shanxi Medical University, Shanxi 030001, PR China. 10. USC Research Center for Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern, Los Angeles, CA, USA.
Abstract
OBJECTIVE: This study is to investigate the role of glucose-regulated protein 78 (GRP78) in the pulmonary microvascular remodeling during hepatopulmonary syndrome (HPS) development. METHODS: The rat models with liver cirrhosis and HPS were induced by multiple pathogenic factors for 4 to 8 wk. The concentrations of alanine transferase (ALT) and endotoxin in plasma were detected in the models, followed by the detection of GRP78 expression. RT-PCR, quantitative real-time PCR and Western blotting were employed to assess the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), respectively. Immunohistochemistry staining was used to examine the expression of a specific vascular marker, factor VIII-related antigen (FVIII-RAg), and several cell proliferation- and apoptosis-related proteins, including CHOP/GADD153, caspase-12, Bcl-2 and nuclear factor (NF)-κB. RESULTS: The levels of endotoxin and ALT in plasma were gradually increased as the disease progressed, so did GRP78, which were in a positive correlation. The expression levels of VEGF (both mRNA and protein) and FVIII-RAg were significantly elevated in the HPS models, indicating active angiogenesis, which was also positively correlated with GRP78 expression. Furthermore, the expression levels of the pro-apoptotic proteins of CHOP/GADD153 and caspase-12 were dramatically decreased, while the anti-apoptotic proteins of Bcl-2 and NF-κB were significantly elevated, in the HPS models. There were also close correlation between these proteins and GRP78. CONCLUSIONS: Over-expression of GRP78 in lungs may be the critical pathogenic factor for HPS. Through promoting cell proliferation and survival and inhibiting apoptosis, GRP78 may promote the pulmonary microvascular remodeling in HPS pathogenesis. Our results provide a potential therapeutic target for clinical prevention and treatment for HPS and related complications.
OBJECTIVE: This study is to investigate the role of glucose-regulated protein 78 (GRP78) in the pulmonary microvascular remodeling during hepatopulmonary syndrome (HPS) development. METHODS: The rat models with liver cirrhosis and HPS were induced by multiple pathogenic factors for 4 to 8 wk. The concentrations of alanine transferase (ALT) and endotoxin in plasma were detected in the models, followed by the detection of GRP78 expression. RT-PCR, quantitative real-time PCR and Western blotting were employed to assess the mRNA and protein expression levels of vascular endothelial growth factor (VEGF), respectively. Immunohistochemistry staining was used to examine the expression of a specific vascular marker, factor VIII-related antigen (FVIII-RAg), and several cell proliferation- and apoptosis-related proteins, including CHOP/GADD153, caspase-12, Bcl-2 and nuclear factor (NF)-κB. RESULTS: The levels of endotoxin and ALT in plasma were gradually increased as the disease progressed, so did GRP78, which were in a positive correlation. The expression levels of VEGF (both mRNA and protein) and FVIII-RAg were significantly elevated in the HPS models, indicating active angiogenesis, which was also positively correlated with GRP78 expression. Furthermore, the expression levels of the pro-apoptotic proteins of CHOP/GADD153 and caspase-12 were dramatically decreased, while the anti-apoptotic proteins of Bcl-2 and NF-κB were significantly elevated, in the HPS models. There were also close correlation between these proteins and GRP78. CONCLUSIONS: Over-expression of GRP78 in lungs may be the critical pathogenic factor for HPS. Through promoting cell proliferation and survival and inhibiting apoptosis, GRP78 may promote the pulmonary microvascular remodeling in HPS pathogenesis. Our results provide a potential therapeutic target for clinical prevention and treatment for HPS and related complications.
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