Sorafenib treatment improves hepatopulmonary syndrome in rats with biliary cirrhosis

2012 ◽  
Vol 124 (7) ◽  
pp. 457-466 ◽  
Author(s):  
Ching-Chih Chang ◽  
Chiao-Lin Chuang ◽  
Fa-Yauh Lee ◽  
Sun-Sang Wang ◽  
Han-Chieh Lin ◽  
...  
Keyword(s):  
Hepatopulmonary Syndrome ◽  
Gas Analysis ◽  
Vegf Receptor ◽  
Biliary Cirrhosis ◽  
Water Control ◽  
Vegf Mrna ◽  
Common Bile Duct Ligation ◽  
Sorafenib Treatment ◽  
Duct Ligation ◽  
Intrapulmonary Shunting

HPS (hepatopulmonary syndrome) is characterized by oxygen desaturation in patients with chronic liver disease. The initiation of HPS comes from abnormal pulmonary vasodilatation and/or angiogenesis. In the present study, we evaluated anti-angiogenesis therapy using sorafenib in experimental HPS animals. HPS was induced by CBDL (common bile duct ligation) in rats. A 2-week 10 mg·(kg of body weight)−1·day−1 treatment regimen of sorafenib or distilled water (control) was initiated 2 weeks after the surgical procedure. Haemodynamics, liver biochemistry, plasma VEGF (vascular endothelial growth factor) measurements and blood gas analysis of the CBDL rats were performed. The livers of the CBDL rats were dissected for histopathology examination, and the lungs were examined by immunohistochemical staining, real-time PCR and Western blot analysis. In another two parallel groups, intrapulmonary shunts were determined. The AaPO2 (alveolar–arterial O2 gradient) and plasma VEGF levels were reduced after sorafenib treatment [AaPO2, 7.2±3.4 mmHg in sorafenib-treated rats compared with 15.3±4.2 mmHg in controls (P=0.004); VEGF, 45.3±2.7 pg/ml in sorafenib-treated rats compared with 54.4±7.7 pg/ml in controls (P=0.021)]. Sorafenib attenuated pulmonary VEGF mRNA and VEGF, VEGFR-2 (VEGF receptor 2), phospho-VEGFR-2 and Akt protein expression. In addition, sorafenib significantly attenuated intrapulmonary angiogenesis and decreased the degree of intrapulmonary shunting by 33.7% (11.2±5.7% in sorafenib-treated rats compared with 16.9±5.9% in controls; P=0.003). Our findings suggest that sorafenib attenuates intrapulmonary shunting and decreases the AaPO2 in CBDL rats, implicating the improvement of HPS in this experimental animal model. The beneficial effect may be attributed to the reduction in intrapulmonary angiogenesis through inhibition of the VEGF/VEGFR-2/Akt pathway.

scholarly journals Effects of Caffeine Treatment on Hepatopulmonary Syndrome in Biliary Cirrhotic Rats

2019 ◽  
Vol 20 (7) ◽  
pp. 1566
Author(s):  
Ching-Chih Chang ◽  
Chiao-Lin Chuang ◽  
Ming-Hung Tsai ◽  
I.-Fang Hsin ◽  
Shao-Jung Hsu ◽  
...  
Keyword(s):  
Mortality Rate ◽  
Liver Fibrosis ◽  
Portal Pressure ◽  
Hepatopulmonary Syndrome ◽  
Gas Analysis ◽  
Common Bile Duct Ligation ◽  
Arterial Blood ◽  
Duct Ligation ◽  
Intrapulmonary Shunting ◽  
Protein Expressions

Hepatopulmonary syndrome (HPS) is a lethal complication of cirrhosis characterized by hypoxia and overt intrapulmonary shunting. In this study, we investigated the effect of caffeine in rats with common bile duct ligation (CBDL)-induced liver cirrhosis and HPS. CBDL rats were randomly allocated to receive caffeine or vehicle for 14 days. On the 28th day after CBDL, mortality rate, hemodynamics, liver, and renal biochemistry parameters and arterial blood gas analysis were evaluated. Lung and liver were dissected for the evaluation of inflammation, angiogenesis and protein expressions. In another series with parallel groups, the intrapulmonary shunting was determined. Caffeine significantly reduced portal pressure (caffeine vs. control: 10.0 ± 3.7 vs. 17.0 ± 8.1 mmHg, p < 0.05) in CBDL rats. The mortality rate, mean arterial pressure, biochemistry data and hypoxia were similar between caffeine-treated and control groups. Caffeine alleviated liver fibrosis and intrahepatic angiogenesis but intrapulmonary inflammation and angiogenesis were not ameliorated. The hepatic VEGF/Rho-A protein expressions were down-regulated but the pulmonary inflammation- and angiogenesis-related protein expressions were not significantly altered by caffeine. Caffeine did not reduce the intrapulmonary shunting, either. Caffeine has been shown to significantly improve liver fibrosis, intrahepatic angiogenesis and portal hypertension in cirrhotic rats, however, it does not ameliorate HPS.

scholarly journals Study of the relation between biliary cirrhosis and hepatopulmonary syndrome and its reversibility among young rats submitted to common bile duct ligation

2018 ◽  
Vol 97 (3) ◽  
pp. 376-377
Author(s):  
Leonardo Ervolino Corbi ◽  
Maria Julia De Aro Braz ◽  
Ana Cristina Aoun Tannuri ◽  
Maria Cecília De Mendonça Coelho ◽  
Suellen Serafini ◽  
...  
Keyword(s):  
Bile Duct ◽  
Common Bile Duct ◽  
Bile Duct Ligation ◽  
Hepatopulmonary Syndrome ◽  
Biliary Cirrhosis ◽  
Common Bile Duct Ligation ◽  
Young Rats ◽  
Duct Ligation

Caspase-3 inhibition prevents the development of hepatopulmonary syndrome in common bile duct ligation rats by alleviating pulmonary injury

2014 ◽  
Vol 35 (4) ◽  
pp. 1373-1382 ◽  
Author(s):  
Bing Chen ◽  
Jiao L. Ning ◽  
Jian T. Gu ◽  
Jian Cui ◽  
Yong Yang ◽  
...  
Keyword(s):  
Bile Duct ◽  
Common Bile Duct ◽  
Caspase 3 ◽  
Bile Duct Ligation ◽  
Hepatopulmonary Syndrome ◽  
Pulmonary Injury ◽  
Common Bile Duct Ligation ◽  
Duct Ligation

scholarly journals MicroRNA-199a-5p Regulates the Proliferation of Pulmonary Microvascular Endothelial Cells in Hepatopulmonary Syndrome

2015 ◽  
Vol 37 (4) ◽  
pp. 1289-1300 ◽  
Author(s):  
Jing Zeng ◽  
Lin Chen ◽  
Bing Chen ◽  
Kaizhi Lu ◽  
Karine Belguise ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Hepatopulmonary Syndrome ◽  
Stress Fibers ◽  
Microvascular Endothelial Cell ◽  
Common Bile Duct Ligation ◽  
Down Regulation ◽  
Rat Serum ◽  
Rac1 Activity ◽  
Duct Ligation ◽  
Microvascular Endothelial

Background/Aims: Pulmonary microvascular endothelial cell (PMVEC) proliferation and angiogenesis contribute to the development of hepatopulmonary syndrome (HPS). MicroRNA-199a-5p (miR-199a-5p) has emerged as a potent regulator of angiogenesis, and its expression levels significantly decrease in the serum of patients with hepatopathy. However, it has not been reported about whether miR-199a-5p might control PMVEC proliferation. Here, we described the miR-199a-5p governing PMVEC proliferation in HPS. Methods: PMVECs were treated with rat serum from common bile duct ligation (CBDL) or sham. MiR-199a-5p mimic or inhibitor was used to change the miR-199a-5p expression. Knockdown of caveolin-1 (Cav-1) was performed using siRNA. NSC-23766 was used to inhibit Rac1 activity. Gene and protein expressions were quantified by qRT-PCR and western blot. Cell proliferation was analyzed by 3H-TdR incorporation and CCK-8 assays. Stress fibers were detected by immunofluorescence. Results: CBDL rat serum induced the down-regulation of miR-199a-5p. Delivery of miR-199a-5p suppressed the CBDL rat serum-induced PMVEC proliferation whereas knockdown of miR-199a-5p promoted PMVEC proliferation. This was accompanied by a decrease and an increase in Cav-1 expression, respectively. Cav-1 siRNA abolished the enhancement of PMVEC proliferation induced by the miR-199a-5p inhibition. Although stress fibers were disrupted in Cav-1 deficient cells, NSC-23766 increased stress fibers and contributed to cell proliferation. Conclusions: CBDL rat serum induced down-regulation of miR-199a-5p in PMVECs, which led to an increase of Cav-1 gene expression. Increased Cav-1 expression, by inhibiting Rac1 activity, led to the formation of stress fibers, which contribute to PMVEC proliferation and thus the pathogenesis of HPS.

scholarly journals Cholangiocyte-Derived Exosomal Long Noncoding RNA PICALM-AU1 Promotes Pulmonary Endothelial Cell EndMT in Hepatopulmonary Syndrome

2021 ◽  
Author(s):  
Congwen Yang ◽  
Yihui Yang ◽  
Yang Chen ◽  
Jian Huang ◽  
Caiyi Li ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Critical Role ◽  
Cell Communication ◽  
Hepatopulmonary Syndrome ◽  
Clinical Problem ◽  
Luciferase Reporter ◽  
Target Cells ◽  
Common Bile Duct Ligation ◽  
Mesenchymal Transition ◽  
Duct Ligation

Abstract Background: Hepatopulmonary syndrome (HPS) is an important clinical problem with limited understanding of disease pathologies. Exosome mediated cell-cell communication can modulate various cellular functions by transferring a variety of intracellular components to target cells. A new lncRNA PICALM-AU1 was found and upregulated in the liver of subjects with HPS. However, the expression and biological functions of the lncRNA PICALM-AU1 are still unknown. Methods: HPS rat model was constructed by common bile duct ligation (CBDL). RNA macroarray was used to analyze the expression differential lncRNAs in HPS rat liver. PICALM-AU1 expression in the serum exosome was measured in 56 HPS patients and in 73 patients with liver cirrhosis but not HPS. qPCR, Fluorescence in situ hybridization were used to analyze PICALM-AU1 expression and location. Virus derived PICALM-AU1 upregulation and down regulation were applied in rats and PMVECs cells. The effects of PICALM-AU1 on PMVECs was determined via CCK8 assay and transwell assay. PICALM-AU1 and miR144-3p relationship was analysis by Dual-luciferase reporter assay.Results: In this study, we found lncRNA PICALM-AU1 expressed in the cholangiocyte of liver, secreted as exosome into the serum. PICALM-AU1 carrying serum exosomes induced endothelial-mesenchymal transition (EndMT) of PMVECs and promoted lung injury. Furthermore, overexpression of PICALM-AU1 significantly suppressed miR144-3p and subsequently induced ZEB1 expression.Conclusions: Taken together, our findings present a road map of targeting the newly identified cholangiocyte-derived exosomal lncRNA PICALM-AU1 plays a critical role in the pathologic angiogenesis of HPS by promoting EndMT and represents a potential therapeutic target for HPS.

Common bile duct ligation in the rat: a model of intrapulmonary vasodilatation and hepatopulmonary syndrome

1997 ◽  
Vol 272 (4) ◽  
pp. G779-G784 ◽  
Author(s):  
M. B. Fallon ◽  
G. A. Abrams ◽  
J. W. McGrath ◽  
Z. Hou ◽  
B. Luo
Keyword(s):  
Portal Hypertension ◽  
Bile Duct ◽  
Gas Exchange ◽  
Common Bile Duct ◽  
Lung Injury ◽  
Bile Duct Ligation ◽  
Hepatopulmonary Syndrome ◽  
Common Bile Duct Ligation ◽  
Arterial Blood ◽  
Duct Ligation

Hepatopulmonary syndrome (HPS) causes impaired oxygenation due to intrapulmonary vasodilatation in patients with cirrhosis. Chronic common bile duct ligation (CBDL) in the rat results in gas-exchange abnormalities similar to HPS, but intrapulmonary vasodilatation has not been evaluated. We assess intrapulmonary vasodilatation, measured in vivo, after CBDL. Sham, 2- and 5-wk CBDL, and 3-wk partial portal vein ligated (PVL) rats had hepatic and lung injury, portal pressure, and arterial blood gases assessed. The pulmonary microcirculation was evaluated by injecting microspheres (size range 5.5-10 microm) intravenously and measuring the size and number of microspheres bypassing the lungs in arterial blood. CBDL animals developed progressive hepatic injury and portal hypertension accompanied by gas-exchange abnormalities and intrapulmonary vasodilatation. PVL animals, with a similar degree of portal hypertension, did not develop intrapulmonary vasodilatation or abnormal gas exchange. No lung injury was observed. CBDL, but not PVL, causes progressive intrapulmonary vasodilatation, which accompanies worsening arterial gas exchange. These findings validate CBDL as a model to study HPS.

scholarly journals Quercetin Treatment Ameliorates Systemic Oxidative Stress in Cirrhotic Rats

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Emanuelle Kerber Vieira ◽  
Silvia Bona ◽  
Fábio Cangeri Di Naso ◽  
Marilene Porawski ◽  
Juliana Tieppo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bile Duct ◽  
Thiobarbituric Acid ◽  
Biliary Cirrhosis ◽  
Thiobarbituric Acid Reactive Substances ◽  
Common Bile Duct Ligation ◽  
Systemic Oxidative Stress ◽  
Duct Ligation ◽  
Secondary Biliary Cirrhosis ◽  
Quercetin Treatment

Our aim was to investigate whether the antioxidant quercetin protects against liver injury and ameliorates the systemic oxidative stress in rats with common bile duct ligation. Secondary biliary cirrhosis was induced through 28 days of bile duct obstruction. Animals received quercetin (Q) after 14 days of obstruction. Groups of control (CO) and cirrhotic (CBDL) animals received a daily 50 mg/kg body weight i.p. injection of quercetin (CO + Q; CBDL + Q) or vehicle (CO; CBDL). Quercetin corrected the reduction in superoxide dismutase (SOD), catalase CAT, and glutathione peroxidase GPx activities and prevented the increase of thiobarbituric acid reactive substances (TBARS), aminotransferases, and alkaline phosphatase in cirrhotic animals. Quercetin administration also corrected the reduced total nitrate concentration in the liver and prevented liver fibrosis and necrosis. These effects suggest that quercetin might be a useful agent to preserve liver function and prevent systemic oxidative stress.

CXCR2 is involved in pulmonary intravascular macrophage accumulation and angiogenesis in a rat model of hepatopulmonary syndrome

2016 ◽  
Vol 131 (2) ◽  
pp. 159-168 ◽  
Author(s):  
Xujiong Li ◽  
Yunxia Chen ◽  
Yongli Chang ◽  
Shufen Li ◽  
Zhongfu Zhao ◽  
...  
Keyword(s):  
Normal Saline ◽  
Venous Pressure ◽  
Hepatopulmonary Syndrome ◽  
Sham Operation ◽  
Sprague Dawley ◽  
Common Bile Duct Ligation ◽  
Pulmonary Tissue ◽  
Post Surgery ◽  
Duct Ligation ◽  
Tnf Α

Hepatopulmonary syndrome (HPS) is a lung complication in various liver diseases, with high incidence, poor prognosis and no effective non-surgical treatments in patients with hepatocirrhosis. Therefore, assessing HPS pathogenesis to explore proper therapy strategies is clinically relevant. In the present study, male Sprague–Dawley rats underwent sham operation or common bile duct ligation (CBDL). Two weeks post-surgery, the following groups were set up for 2 weeks of treatment: sham + normal saline, CBDL + CXCR2 antagonist SB225002, CBDL + tumour necrosis factor α (TNF-α) antagonist PTX and CBDL + normal saline groups. Liver and lung tissues were collected after mean arterial pressure (MAP) and portal venous pressure (PVP) measurements. Haematoxylin and eosin (H&E) staining (lung) and Masson staining (liver) were performed for pathological analyses. Finally, pulmonary tissue RNA and total protein were assessed for target effectors. The mRNA and protein levels of CXCR2 were significantly increased in the pulmonary tissue of CBDL rats. What's more, CXCR2 inhibition by SB225002 reduced the expression of CD68 and von Willebrand factor (vWf) in CBDL rats. Importantly, CXCR2 inhibition suppressed the activation of Akt and extracellular signal-regulated kinase (ERK) in CBDL rats. Antagonization of TNF-α with PTX down-regulated the expression of CXCR2. During HPS pathogenesis in rats, CXCR2 might be involved in the accumulation of pulmonary intravascular macrophages and angiogenesis, possibly by activating Akt and ERK, with additional regulation by TNF-α that enhanced pulmonary angiogenesis by directly acting on the pulmonary tissue. Finally, the present study may provide novel targets for the treatment of HPS.

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