Glucose-regulated protein 78 may play a crucial role in promoting the pulmonary microvascular remodeling in a rat model of hepatopulmonary syndrome.
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.
Pathophysiology Department of Changzhi Medical College, Shanxi 046000, PR China. Electronic address: zhanghy2001@163.com.
Huiying
H
Zhang
ICU of the Second Hospital of Shanxi Medical University, Shanxi 030001, PR China.
Minli
M
Lv
Institute of Hepatology of Changzhi Medical College, Shanxi 046000, PR China.
Zhongfu
Z
Zhao
Pathophysiology Department of Changzhi Medical College, Shanxi 046000, PR China.
Jiantao
J
Jia
Pathophysiology Department of Changzhi Medical College, Shanxi 046000, PR China.
Lili
L
Zhang
Pathology Department of Changzhi Medical College, Shanxi 046000, PR China.
Peng
P
Xiao
Functional Laboratory of Changzhi Medical College, Shanxi 046000, PR China.
Limin
L
Wang
Physiology Department of Changzhi Medical College, Shanxi 046000, PR China.
Chen
C
Li
Pathophysiology Department of Changzhi Medical College, Shanxi 046000, PR China.
Jingquan
J
Ji
Pathophysiology Department of Changzhi Medical College, Shanxi 046000, PR China.
Xiaoxia
X
Tian
Physiology Department of Changzhi Medical College, Shanxi 046000, PR China.
Xujiong
X
Li
Functional Laboratory of Changzhi Medical College, Shanxi 046000, PR China.
Yimin
Y
Fan
Pharmacology Department of Changzhi Medical College, Shanxi 046000, PR China.
Lina
L
Lai
Physiology Department of Changzhi Medical College, Shanxi 046000, PR China.
Yan
Y
Liu
Pathophysiology Department of Changzhi Medical College, Shanxi 046000, PR China.
Baohong
B
Li
Functional Laboratory of Changzhi Medical College, Shanxi 046000, PR China.
Cuiying
C
Zhang
Institute of Hepatology of Changzhi Medical College, Shanxi 046000, PR China.
Mingshe
M
Liu
Institute of Hepatology of Shanxi Medical University, Shanxi 030001, PR China.
Jianhong
J
Guo
Institute of Hepatology of Shanxi Medical University, Shanxi 030001, PR China.
Dewu
D
Han
USC Research Center for Liver Disease, Department of Medicine, Keck School of Medicine, University of Southern, Los Angeles, CA, USA.
Cheng
C
Ji
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D053454:Caspase 12 / Q000378:metabolism; D004195:Disease Models, Animal; D006360:Heat-Shock Proteins / Q000378:metabolism*; D020065:Hepatopulmonary Syndrome / Q000097:blood / Q000378:metabolism* / Q000503:physiopathology*; D008168:Lung / Q000098:blood supply / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051742:Transcription Factor CHOP / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP
D000410:Alanine Transaminase; D053454:Caspase 12; D006360:Heat-Shock Proteins; D016328:NF-kappa B; D051742:Transcription Factor CHOP; D042461:Vascular Endothelial Growth Factor A; C497251:Ddit3 protein, rat; C051684:GRP78 protein, rat; D000091342:Endoplasmic Reticulum Chaperone BiP; C467498:vascular endothelial growth factor A, rat
Endotoxin; Glucose-regulated protein 78; Hepatopulmonary syndrome; Liver cirrhosis; Pulmonary microvascular remodeling