Development Of Hepatopulmonary Syndrome Research Articles

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Liver cirrhosis is often accompanied by complications from the pulmonary system. These include hydrothorax, portopulmonary hypertension and hepatopulmonary syndrome. Hepatic hydrothorax affects about 6-10% of patients with end-stage disease, which results in the passage of ascetic fluid into the pleural space through diaphragm defects. The common cause of the hepatopulmonary syndrome and portopulmonary hypertension is portal hypertension and portosystemic shunting, indicating that vasoactive and angiogenetic factors originating from the liver normally control the pulmonary circulation. Portopulmonary hypertension is like pulmonary arterial hypertension, which develops against the background of portal hypertension as a result of chronic liver disease or without other causes of increased pressure in the pulmonary vessels. The prevalence of portopulmonary hypertension ranges from 2% to 8.5% among patients with portal hypertension and is associated with a poor prognosis. Hepatopulmonary syndrome is characterized by intrapulmonary dilatation of microvessels, which causes intrapulmonary shunting and leads to impaired gas exchange in liver diseases, and is associated with a decrease in the quality and duration of life in patients with cirrhosis. Nitric oxide overproduction and angiogenesis seem to be the hallmarks of a complicated pathogenetic mechanism, leading to intrapulmonary shunting and ventilation-perfusion mismatch. A classification of hepatopulmonary syndrome according to the severity of hypoxemia has been suggested. Hepatopulmonary syndrome includes a triad: hepatic dysfunction and / or portal hypertension, dilatation of intrapulmonary vessels, and increased alveolar-arterial oxygen gradient. The prevalence of hepatopulmonary syndrome varies depending on the study groups from 5% to 30%. The most common symptom of the complication is shortness of breath, but in most cases, hepatopulmonary syndrome is asymptomatic. A decrease in oxygen saturation less than 96% corresponds to a decrease in PaO2<70 mm Hg and testifies to the possible development of hepatopulmonary syndrome. In the case of a positive screening, the patient should undergo arterial blood gas analysis, which helps to determine PaO2 and alveolar to arterial oxygen gradient. Conclusion. Contrast-enhanced echocardiography with agitated saline is the gold standard in the diagnosis of intrapulmonary dilatation. The only effective treatment for hepatopulmonary syndrome is liver transplantation. Complete recovery of hepatopulmonary syndrome after liver transplantation is observed within a year in most patients with cirrhosis and hepatopulmonary syndrome

Platypnea: оne more type position shortness of breath

The article presents modern data on the causes of platypnea, methods of its diagnosis and treatment. The data on the development of platypnea syndrome are given not only in cardiac pathology, but also in severe liver diseases with the development of hepatopulmonary syndrome and chronic obstructive pulmonary disease of a severe course.

AMD3100 treatment attenuates pulmonary angiogenesis by reducing the c-kit (+) cells and its pro-angiogenic activity in CBDL rat lungs

Recent studies have shown that pulmonary angiogenesis is an important pathological process in the development of hepatopulmonary syndrome (HPS), and growing evidence has indicated that Stromal cell-derived factor 1/C-X-C chemokine receptor type 4 (SDF-1/CXCR4) axis is involved in pulmonary vascular disease by mediating the accumulation of c-kit+ cells. This study aimed to test the effect of AMD3100, an antagonist of CXCR4, in HPS pulmonary angiogenesis. Common bile duct ligation (CBDL) rats were used as experimental HPS model and were treated with AMD3100 (1.25mg/kg/day, i.p.) or 0.9% saline for 3weeks. The sham rats underwent common bile duct exposure without ligation. The c-kit+ cells accounts and its angiogenic-related functions, prosurvival signals, pulmonary angiogenesis and arterial oxygenation were analysed in these groups. Our results showed that pulmonary SDF-1/CXCR4, Akt, Erk and VEGF/VEGFR2 were significantly activated in CBDL rats, and the numbers of circulating and pulmonary c-kit+ cells were increased in CBDL rats compared with control rats. Additionally, the angiogenic-related functions of c-kit+ cells and pulmonary microvessel counts were also elevated in CBDL rats. CXCR4 inhibition reduced pulmonary c-kit+ cells and microvessel counts and improved arterial oxygenation within 3weeks in CBDL rats. The pulmonary prosurvival signals and pro-angiogenic activity of c-kit+ cells were also down-regulated in AMD3100-treated rats. In conclusion, AMD3100 treatment attenuated pulmonary angiogenesis in CBDL rats and prevented the development of HPS via reductions in pulmonary c-kit+ cells and inhibition of the prosurvival signals. Our study provides new insights in HPS treatment.

Prevalence and impact on survival of hepatopulmonary syndrome and cirrhotic cardiomyopathy in a cohort of cirrhotic patients

Extrahepatic complications of cirrhosis increase the risk for decompensation of the liver disease and death. Previous studies show common pathogenetic mechanisms involved in the development of hepatopulmonary syndrome and cirrhotic cardiomyopathy. We aimed to assess the link between these entities and their effect on disease-related patient morbidity and mortality. Seventy-four consecutive cirrhotic patients without prior history of cardiovascular and pulmonary disease were included in a prospective observational study. Routine blood work, arterial blood gas analysis, pulse oximetry measurements, N-terminal pro-brain natriuretic peptide levels and contrast enhanced echocardiography examination with tissue Doppler imaging were performed in all patients. Patients were followed up for a median of 6 months and disease-related adverse events and death were the main outcomes tested. Statistical analysis was conducted according to the presence of hepatopulmonary syndrome or cirrhotic cardiomyopathy. Hepatopulmonary syndrome was diagnosed in 17 patients (23%) and cirrhotic cardiomyopathy in 30 patients (40.5%). There was no association between the presence of cirrhotic cardiomyopathy and the existence of mild or moderate hepatopulmonary syndrome. No echocardiographic parameters were useful in predicting the presence of hepatopulmonary syndrome. N-terminal pro-brain natriuretic peptide levels and length of QT interval did not aid in diagnosis of cirrhotic cardiomyopathy. Neither entity had significant influence on disease-related outcomes in the follow-up period. Hepatopulmonary syndrome and cirrhotic cardiomyopathy are independent complications arising in cirrhosis and have a limited influence on morbidity and mortality on a pre-liver transplantation population.

Expression of the 78 kD glucose-regulated protein is induced by endoplasmic reticulum stress in the development of hepatopulmonary syndrome

ObjectiveThis study is to explore the role of 78kD glucose-regulated protein (GRP78) in the development of hepatopulmonary syndrome (HPS) in rats. MethodsThe rat model of liver cirrhosis and HPS were induced with multiple pathogenic factors. Hematoxylin and eosin (H & E) staining was performed to detect the pathological changes of the lung and liver tissues. The levels of alanine transferase (ALT), endotoxin, and tumor necrosis factor-α (TNF-α) in plasma and TNF-α and malondialdehyde (MDA) in lung tissues were detected. RT-PCR and Western blotting were conducted to detect the mRNA and protein expression levels of GRP78 in lungs. ResultsThe plasma endotoxin level was gradually increased as HPS developed, and the mRNA and protein expression levels of GRP78 in lungs were also increased as the disease progressed. The levels of ALT and TNF-α in plasma and the contents of TNF-α and MDA in lung tissues were gradually increased along with the disease progression, with a strong positive correlation. Compared with controls, the plasma TNF-α level and the mRNA and protein expression levels of GRP78 in lung tissues were significantly higher in rats with HPS. The levels of endotoxin and ALT in plasma and the level of MDA in lungs were significantly higher in rats with HPS than controls. ConclusionsThe increased GRP78 expression is indicative of endoplasmic reticulum stress response during HPS, which may play an important role in the disease pathogenesis.

Role of serine threonine protein kinase-1 and Smad3 in lung tissues in development of hepatopulmonary syndrome in rats

Objective To investigate the role of serine threonine protein kinase-1 (Akt1) and Smad3 in lung tissues in development of hepatopulmonary syndrome in rats.Methods Seventy-two healthy male SpragueDawley rats,aged 3-4 months,weighing 200-250 g,were randomly divided into 3 groups (n=24 each):control group (C group),sham operation group (S group) and common bile duct ligation (CBDL) group.The rats were anesthetized with 3％ pentobarbital sodium 45 mg/kg.In group CBDL,laparotomy was performed,the common bile duct was ligated and then the abdomen was closed,while the common bile duct was only exposed,but not ligated and then the abdomen was closed in group S.At 1st,3rd and 5th weeks (T1-3),8 rats were chosen randomly in each group and blood samples were obtained from the abdominal aorta for blood gas analysis.The rats were then sacrificed and lungs were isolated to detect the expression of Aktl and Smad3 mRNA and protein in lung tissues (by RT-PCR and Western blot).The lung tissues were sliced and stained with hematoxylin eosin for examination of the pathological changes of pulmonary capillaries.Results Compared with C and S groups,the expression of Akt1 and Smad3 mRNA and protein in lung tissues was significantly up-regulated at T2,3,and alveolar-arterial oxygen tension difference was increased at T3 in CBDL group (P ＜ 0.05).The pulmonary capillary was obviously dilated at T3 in CBDL group.Conclusion The expression of Akt1 and Smad3 in lung tissues is up-regulated,which may be one of the mechanisms of development of hepatopulmonary syndrome in rats. Key words: Hepatopulmonary syndrome ; Lung ; Protein-serine-threonine kinases ; Smad3 protein

Resolution of hepatopulmonary syndrome after ligation of a portosystemic shunt in a pediatric patient with an Abernethy malformation

This report describes a case of Abernethy malformation associated with hepatopulmonary syndrome, which was resolved after shunt ligation. The clinical course indicated that hepatopulmonary syndrome can develop in Abernethy malformation in which liver function and portal pressure is normal, and liver transplantation is not the exclusive therapy for hepatopulmonary syndrome. The levels of endotoxin and endothelin 1 in the shunt blood were high, whereas those of tumor necrosis factor alpha and interleukin-1beta were within reference range. Although pathogenesis of hepatopulmonary syndrome remains unknown, the findings in this case suggest that bacterial translocation as well as elevated endothelin 1 may play a causal role in development of hepatopulmonary syndrome.

Intestinal endotoxemia plays a central role in development of hepatopulmonary syndrome in a cirrhotic rat model induced by multiple pathogenic factors

瞄准：描绘在肝肺症候群(HPS ) 和肝的机能障碍的度的严厉之间的关联，并且探索肠的 endotoxemia (IETM ) 怎么在肝脏硬化症的老鼠影响 HPS 的发展。方法：男威斯特老鼠用包含玉米面粉，猪油，胆固醇，和酒精的一本食谱被喂并且每二天与 CCl4 油答案皮下地注射了让 8 wk 导致 HPS 的典型肝硬化和开发。动物也被给氮的氧化物(没有)生产禁止者， Nomega-nitro-L-arginine 甲基酉旨(L名字) intraperitoneally ，并且 i NOS 禁止者，经由从到 第6 或 第8 wk 的目的 第4 wk 的结束每日的管饲法的氨基胍水疗院氯化物( AG )，或一个 HO-1 禁止者，锌原卟啉( ZnPP ) intraperitoneally 在杀死以前的 12 h 。血，肝和肺纸巾被取样。结果：到在肝脏硬化症的老鼠的肝的肺 paralleled 的组织学的恶化。肺的 capillaries 的数字日益增多地从 6.1 +/- 被增加 1.1 (数 / 提起) 在到 14.5 +/- 的第 4 wk 2.4 (数 / 提起) 在在肝脏硬化症的老鼠的第 8 wk。增加的肺的 capillaries 与脂肪的多糖(LPS ) 的增加的血层次被联系(0.31 +/- 0.08 EU/mL 对控制 0.09 +/- 0.03 EU/mL ) ，丙氨酸转移酶(中高音， 219.1 +/- 17.4 U/L 对控制 5.9 +/- 2.2 U/L ) 并且门静脉压力。与正常对照动物相比，在在 第8 wk 的肝脏硬化症的老鼠的 bronchoalveolar 洗室年龄液体( BALF )的全部的房间的数字没被改变，但是巨噬细胞的数字和到全部的房间的巨噬细胞的比率被将近2褶层增加，可诱导的氮的氧化物 synthase ( i NOS )和内皮的氮的氧化物 synthase ( eNOS )的蛋白质表示开始在 第4 wk 显著地增加，并且在肝脏硬化症的老鼠的肺在 第8 wk 到达了它的山峰。i NOS 表示的增加看起来比 eNOS 的快。NO2-/NO3- 也被增加，它被相关到 i NOS 的增加(r = 0.7699， P < 0.0001 ) 并且 eNOS (r = 0.5829， P < 0.002 ) 。eNOS 和 i NOS 的 mRNA 表示与他们的蛋白质表示高度一致。结论：由增加的肺

Intestinal endotoxemia plays a central role in development of hepatopulmonary syndrome in a cirrhotic rat model induced by multiple pathogenic factors

To characterize the correlation between severity of hepatopulmonary syndrome (HPS) and degree of hepatic dysfunction, and to explore how intestinal endotoxemia (IETM) affects the development of HPS in cirrhotic rats. Male Wister rats were fed with a diet containing maize flour, lard, cholesterol, and alcohol and injected subcutaneously with CCl(4) oil solution every two days for 8 wk to induce typical cirrhosis and development of HPS. The animals were also given a nitric oxide (NO) production inhibitor, N(omega)-nitro-L-arginine methyl ester (L-NAME) intraperitoneally, and an iNOS inhibitor, aminoguanidine hydrochloride (AG) via gavage daily from the end of the 4th wk to the end of the 6th or 8th wk, or a HO-1 inhibitor, zinc protoporphyrin (ZnPP) intraperitoneally 12 h prior to killing. Blood, liver and lung tissues were sampled. Histological deterioration of the lung paralleled to that of the liver in the cirrhotic rats. The number of pulmonary capillaries was progressively increased from 6.1 +/- 1.1 (count/filed) at the 4th wk to 14.5 +/- 2.4 (count/filed) at the 8th wk in the cirrhotic rats. Increased pulmonary capillaries were associated with increased blood levels of lipopolysaccharide (LPS) (0.31 +/- 0.08 EU/mL vs control 0.09 +/- 0.03 EU/mL), alanine transferase (ALT, 219.1 +/- 17.4 U/L vs control 5.9 +/- 2.2 U/L) and portal vein pressure. Compared with normal control animals, the number of total cells in bronchoalveolar lavage fluid (BALF) of the cirrhotic rats at the 8th wk was not changed, but the number of macrophages and the ratio of macrophages to total cells were increased by nearly 2-fold, protein expression of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) started to increase significantly at the 4th wk, and reached its peak at the 8th wk in the lung of cirrhotic rats. The increase of iNOS expression appeared to be quicker than that of eNOS. NO(2)(-)/NO(3)(-) was also increased, which was correlated to the increase of iNOS (r = 0.7699, P < 0.0001) and eNOS (r = 0.5829, P < 0.002). mRNA expression of eNOS and iNOS was highly consistent with their protein expression. Progression and severity of HPS as indicated by both increased pulmonary capillaries and histological changes are closely associated with LPS levels and progression of hepatic dysfunction as indicated by increased levels of ALT and portal vein pressure. Intestinal endotoxemia plays a central role in the development of HPS in the cirrhotic rat model by inducing NO and/or CO.

Cholangiocyte Endothelin 1 and Transforming Growth Factor β1 Production in Rat Experimental Hepatopulmonary Syndrome

Cholangiocyte Endothelin 1 and Transforming Growth Factor β1 Production in Rat Experimental Hepatopulmonary Syndrome

Cholangiocyte Endothelin 1 and Transforming Growth Factor β1 Production in Rat Experimental Hepatopulmonary Syndrome

Hepatic production and release of endothelin 1 plays a central role in experimental hepatopulmonary syndrome after common bile duct ligation by stimulating pulmonary endothelial nitric oxide production. In thioacetamide-induced nonbiliary cirrhosis, hepatic endothelin 1 production and release do not occur, and hepatopulmonary syndrome does not develop. However, the source and regulation of hepatic endothelin 1 after common bile duct ligation are not fully characterized. We evaluated the sources of hepatic endothelin 1 production after common bile duct ligation in relation to thioacetamide cirrhosis and assessed whether transforming growth factor beta1 regulates endothelin 1 production. Hepatopulmonary syndrome and hepatic and plasma endothelin 1 levels were evaluated after common bile duct ligation or thioacetamide administration. Cellular sources of endothelin 1 were assessed by immunohistochemistry and laser capture microdissection of cholangiocytes. Transforming growth factor beta1 expression and signaling were assessed by using immunohistochemistry and Western blotting and by evaluating normal rat cholangiocytes. Hepatic and plasma endothelin 1 levels increased and hepatopulmonary syndrome developed only after common bile duct ligation. Hepatic endothelin 1 and transforming growth factor beta1 levels increased over a similar time frame, and cholangiocytes were a major source of each peptide. Transforming growth factor beta1 signaling in cholangiocytes in vivo was evident by increased phosphorylation and nuclear localization of Smad2, and hepatic endothelin 1 levels correlated directly with liver transforming growth factor beta1 and phosphorylated Smad2 levels. Transforming growth factor beta1 also stimulated endothelin 1 promoter activity, expression, and production in normal rat cholangiocytes. Cholangiocytes are a major source of hepatic endothelin 1 production during the development of hepatopulmonary syndrome after common bile duct ligation, but not in thioacetamide-induced cirrhosis. Transforming growth factor beta1 stimulates cholangiocyte endothelin 1 expression and production. Cholangiocyte-derived endothelin 1 may be an important endocrine mediator of experimental hepatopulmonary syndrome.

Experimental study on the role of endotoxin in the development of hepatopulmonary syndrome

To evaluate the role of intestinal endotoxemia in the genesis of hepatopulmonary syndrome. A rat model of cirrhosis was prepared with the method of compound factors. At the end of the eighth week, rats with cirrhosis were treated with 300 microg LPS/100 g body weight, and 1 g/rat of glycine about four h prior to LPS. After three h of LPS treatment, blood and tissues were collected for various measurements. Kupffer cells were isolated from male Wistar rats and cultured, and divided into five groups. Supernatant was harvested at 3 h after treatment with LPS for measurement of tumor necrosis factor-alpha (TNF-alpha). Our results showed that in rats with cirrhosis, slowed and deepened breath with occasional pause was. PaO2, PaCO2 and standard bicarbonate (SB) in arterial blood were decreased. Arterial O2 and actual bicarbonate (AB) were markedly decreased. There was a close correlation between decreased O2 and endotoxin. Metabolic acidosis accompanying respiratory alkalosis was the primary type of acid-base imbalance. The alveolar-arterial oxygen gradient was sharply widened. Massive accumulation of giant macrophages in the alveolar spaces and its wall and widened alveolar wall architecture were observed. The number of bacterial translocations in mesenteric lymph nodes increased. The ratio of TC99M-MAA brain-over-lung radioactivity rose. Endotoxin, and TNF-alpha, endothelin-1 (ET-1), nitric oxide (NO) in plasma and ET-1, carbon monoxide (CO) in lung homogenates increased. After administration of a given dosage of LPS in rats with cirrhosis, various pathological parameters worsened. Plasma level of endotoxin was related to TNF-alpha, ET-1, NO in plasma and ET-1, NO, CO in lung homogenates. TNF-alpha level was related to ET-1 and NO in plasma and lung homogenates and CO in lung homogenate as well. The level of TNF-alpha increased after infusion of LPS into culture supernatant of Kupffer cells in vitro. However, TNF-alpha significantly decreased after pretreatment with glycine, PD98059 and SB212850. Glycine could antagonize the effect of LPS in vivo and in vitro. Intestinal endotoxemia accompanying by cirrhosis may be an important mechanism in the development of hepatopulmonary syndrome in rats. Overproduction of TNF-alpha due to endotoxin stimulation of Kupffer cells via mitogen-activated protein kinase (MAPK) signal transduction pathway may be a major mechanism mediating the pathologic alterations of hepatopulmonary syndrome.

Development of hepatopulmonary syndrome and portopulmonary hypertension in a paediatric liver transplant patient

Hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH) are pulmonary vascular disorders which occur in patients with severe liver disease and/or portal hypertension. Although these syndromes are frequently diagnosed in patients undergoing assessment for liver transplantation, they seldom occur in the same patient. This report describes a female paediatric patient, born with extra-hepatic biliary atresia, who required liver transplantation, at the age of 15, for secondary biliary cirrhosis. She had severe HPS prior to her first liver transplant, which resolved rapidly following surgery, as well as indirect evidence for PPH. She required a second liver transplant 1 yr later for chronic rejection. Whilst evaluating the patient for a third liver transplant, 4 yr later, severe PPH was discovered. The patient died 3 months later from right heart failure. HPS and PPH may coexist however they may show differing responses to liver transplantation with progression of PPH despite the resolution of HPS.

Transjugular intrahepatic portosystemic shunt improves oxygenation in hepatopulmonary syndrome

Hepatopulmonary syndrome is a complication of chronic liver disease in which arterial hypoxemia results from abnormalities in pulmonary blood flow. Severe hypoxemia can lead to clinical deterioration and death. Although the etiology is unknown, portal hypertension seems to be an important factor in the development of hepatopulmonary syndrome. No effective pharmacological therapy has been identified, but liver transplantation may be curative. Arterial hypoxemia may complicate transplant surgery, however, and resolution of the syndrome after liver transplantation is performed may be delayed. In addition, it seems that complete reversal of oxygenation abnormalities after liver transplantation is performed is unpredictable. We describe a patient with hepatopulmonary syndrome who noted improvement in symptoms of dyspnea after the placement of a transjugular intrahepatic portosystemic shunt Arterial oxygenation and calculated shunt fraction improved significantly during the follow-up period, and liver transplantation was subsequently performed without difficulty. Portal decompression using transjugular intrahepatic portosystemic shunt may represent a palliative therapy for hepatopulmonary syndrome in patients awaiting liver transplantation.