miR144-3p inhibits PMVECs excessive proliferation in angiogenesis of hepatopulmonary syndrome via Tie2.

BACKGROUND/AIM: Increasing evidence show microRNAs (miRNAs) are associated with hepatopulmonary syndrome (HPS). The aim of this study was to investigate the role of miR-144 in the angiogenesis of HPS, as well as to identify its underlying mechanism. METHODS: The expression levels of miR-144-3p were assessed in pulmonary micro-vascular endothelial cells (PMVECs), as well as in lung tissues from rats with HPS. We predicted the potential target of miR-144-3p. Tyrosine kinase 2(Tie2) was identified as a target gene of miR144-3p, which has an essential role in the angiogenesis of lung vessel. In addition, the effects of miR-144-3p regulated on Tie2 was examined. The upregulation and down-regulation of miR-144-3p can affect the proliferation of PMVECs. RESULTS: We found that the levels of miR-144-3p were frequently downregulated in HPS tissues and cell lines, and overexpression of miR-144-3p dramatically inhibited PMVECs proliferation and cell cycle. We further verified the Tie2 as a novel and direct target of miR-144-3p in HPS. CONCLUSION: miR-144-3p can negatively regulate PMVECs proliferation by Tie2 expression. In addition, overexpression of miR-144-3p may prove beneficial as a therapeutic strategy for HPS treatment.

Congenital extrahepatic portosystemic shunt: an underdiagnosed but treatable cause of hepatopulmonary syndrome.

Congenital extrahepatic portosystemic shunt (CEPS) is a rare malformation of the mesenteric vasculature, which may lead to severe complications. In this report, we describe a case series of three children with type II CEPS (presenting as hypoxemia) and hepatopulmonary syndrome (HPS). The first patient was a 4-year-old male who did not receive any specific treatment and subsequently died of brain abscess 5 years after the diagnosis. The second patient was a 10-year-old female with a 5-year history of cyanosis and dyspnea on exertion. She had partial regression of hypoxemia and improved exercise tolerance at 8 months after a surgical shunt closure. The third patient was a 4-year-old male with a 3-year history of cyanosis and decreased exercise tolerance. He had full regression of hypoxemia at 3 months after a transcatheter shunt closure. CONCLUSION: These results indicate that CEPS may present in children with unexplained hypoxemia, which may lead to devastating clinical consequences. Closure of portosystemic shunts may result in resolution of HPS in type II CEPS and the length of period for resolution varies depending on the severity of HPS. WHAT IS KNOWN: Congenital extrahepatic portosystemic shunt (CEPS) is a rare cause of hepatopulmonary syndrome (HPS). There have been few reports in the literature about the management and outcome of HPS in children with CEPS. WHAT IS NEW: CEPS may present in children with unexplained hypoxemia, which may lead to devastating clinical consequences. Closure of portosystemic shunts may result in resolution of HPS in type II CEPS.

MiR26-5p inhibits pathological pulmonary microvascular angiogenesis via down-regulating WNT5A.

Objectives: Pathological micro angiogenesis is a key pathogenic factor in pulmonary diseases such as pulmonary hypertension and hepatopulmonary syndrome. More and more pieces of evidence show that excessive proliferation of pulmonary microvascular endothelial cells is the key event of pathological micro angiogenesis. The purpose of this research is to reveal the mechanism of miR26-5p regulating pulmonary microvascular hyperproliferation. Materials and Methods: Hepatopulmonary syndrome rat model was made by common bile duct ligation. HE and IHC staining were used for analysis of the pathology of the rat. CCK8, transwell, and wound healing assay were used to assess miR26-5p or target gene WNT5A functioned toward PMVECs. microRNA specific mimics and inhibitors were used for up/down-regulated miR26-5p expression in PMVECs. Recombinant lentivirus was used for overexpression/knockdown WNT5A expression in PMVECs. And the regulation relationship of miR26-5p and WNT5A was analyzed by dual-luciferase reporter assay. Results: qPCR showed that miR26-5p was significantly down-regulated in the course of HPS disease. Bioinformatics data showed that WNT5A was one of the potential key target genes of miR26-5p. Immunohistochemistry and qPCR analysis showed that WNT5A was largely expressed in pulmonary microvascular endothelial cells, in addition, this molecule was significantly up-regulated with the progression of the disease. Furthermore, dual luciferase reporter assay showed that miR26-5p could bind to WNT5A 3 'UTR region to inhibit WNT5A synthesis. Conclusion: The results suggested MiR26-5p negatively regulated PMVECs proliferation and migration by WNT5A expression. Overexpression of miR26-5p may be a potentially beneficial strategy for HPS therapy.

When common things aren't so common: A case report of hepatopulmonary syndrome.

A 60-year-old smoker with a history of liver cirrhosis and chronic obstructive pulmonary syndrome (COPD) presented with hypoxic respiratory failure. This was felt secondary to an exacerbation of COPD. Despite treatment, the patient required 10 L of oxygen to achieve saturations of 88% on ambulation. Interstitial lung disease, pulmonary emboli and pulmonary hypertension were excluded as potential aetiologies of hypoxia. Given the history of cirrhosis, hepatopulmonary syndrome was postulated. Contrast echocardiography suggested an extracardiac shunt; a technetium-99m macroaggregated albumin scan confirmed the diagnosis.

Indicators Of Hepatopulmonary Syndrome In Patients With Portal Hypertension. Its Various Aetiologies, Clinical Presentations And Outcome.

BACKGROUND: Hepatopulmonary syndrome is severe pulmonary vascular complication of chronic liver disease requiring liver transplant. This study was conducted to evaluate different indicators of HPS in patients with portal hypertension, its varied aetiologies, clinical features & outcome. METHODS: Hospital based descriptive study, 203 patients were enrolled, divided in to 2 groups positive and negative on the basis of presence or absence of HPS as per diagnostic criteria. RESULTS: It included 203 patients with portal Hypertension of varied aetiologies. Age range was 8.76±3.69 years. 54.7% were male & 45.3% female. Commonest diagnosis for portal hypertension was portal vein thrombosis in 48 (23.6%) while Least common was biliary atresia seen in 6 (3%) of cases. Fifteen patients were included in Positive group and 188 in negative group. Clinical & laboratory parameters in order of frequency in positive group were hypoxia & cyanosis in 100% & 93.3% followed by dyspnoea & grade 4 clubbing in 86.6% patients (p<0.001). Child scoring was also done in all patients. In negative group 7 (3.7%) had dyspnoea, I (0.53%) had grade 4 clubbing while none showed evidence of hypoxia or cyanosis (p<0.001). Three patients underwent successful liver transplant. One patient of biliary atresia & another of CHF expired. CONCLUSIONS: In All children with CLD and/or PHT with unexplained dyspnoea, cyanosis and grade 4 clubbing, HPS should be suspected. It is an indication for early LT even in absence of liver failure.

Pulmonary Complications in Patients with Liver Cirrhosis.

Patients with advanced chronic liver diseases, particularly with decompensated liver cirrhosis, can develop specific pulmonary complications independently of any pre-existing lung disease. Especially when dyspnea occurs in combination with liver cirrhosis, patients should be evaluated for hepato-pulmonary syndrome (HPS), porto-pulmonary hypertension (PPHT), hepatic hydrothorax and spontaneous bacterial empyema, which represent the clinically most relevant pulmonary complications of liver cirrhosis. Importantly, the pathophysiology, clinical features, diagnosis and the corresponding therapeutic options differ between these entities, highlighting the role of specific diagnostics in patients with liver cirrhosis who present with dyspnea. Liver transplantation may offer a curative therapy, including selected cases of HPS and PPHT. In this review article, we summarize the pathogenesis, clinical features, diagnostic algorithms and treatment options of the 4 specific pulmonary complications in patients with liver cirrhosis.

Krüppel-like factor 6 mediates pulmonary angiogenesis in rat experimental hepatopulmonary syndrome and is aggravated by bone morphogenetic protein 9.

Hepatopulmonary syndrome (HPS) is a serious pulmonary vascular disease derived from chronic liver disease, and its key pathogenesis is angiogenesis. Krüppel-like factor 6 (KLF6) mediates physiological repair and remodeling during vascular injury. However, the role of KLF6 in pulmonary microvascular endothelial cells (PMVECs) during angiogenesis of HPS and its underlying mechanism in HPS have not been investigated. Common bile duct ligation (CBDL) in rats can replicate pulmonary vascular abnormalities of human HPS. Here, we found that advanced pulmonary angiogenesis and pulmonary injury score coincided with the increase of KLF6 level in PMVECs of CBDL rat; KLF6 in PMVECs was also induced while cultured with CBDL rat serum in vitro Inhibition of KLF6 dramatically suppressed PMVEC-mediated proliferation, migration and tube formation in vivo; this may be related to the downregulation of activin receptor-like kinase-1 (ALK1) and endoglin (ENG), which are transacted by KLF6. Bone morphogenetic protein 9 (BMP9) enhanced the expression of KLF6 in PMVECs and was involved in the angiogenesis of HPS. These results suggest that KLF6 triggers PMVEC-mediated angiogenesis of HPS and is aggravated by BMP9, and the inhibition of the BMP9/KLF6 axis may be an effective strategy for HPS treatment.

Protective Effects of Emodin on Lung Injuries in Rat Models of Liver Fibrosis.

OBJECTIVE: The aim of this study is to investigate the protective effects of emodin (EMD) on the lung injuries in the rat models of liver fibrosis. METHODS: Liver fibrosis was established in rats and the effect of intervention using EMD treatment was determined. Liver and lung weight coefficients were measured and lung content of TNF-α (tumor necrosis factor α), MDA (malondialdehyde), NO (nitric oxide), and ONOO- (peroxynitrite) were determined. Finally, histopathological changes were evaluated. RESULTS: Compared with the normal control group, the lung weight coefficient was significantly increased in the fibrosis model group. Moreover, pulmonary edema and inflammatory responses were observed. Levels of TNF-α, MDA, NO, and ONOO- in the lung homogenate were significantly increased in the fibrosis model group. After EMD treatment, the lung weight coefficients were significantly reduced. Moreover, pathological changes in the lung tissue were dramatically alleviated. Levels of TNF-α, MDA, NO, and ONOO- were significantly decreased. CONCLUSION: EMD exhibits protective effects against lung injuries in a rat model of liver fibrosis.

MiR145-5p inhibits proliferation of PMVECs via PAI-1 in experimental hepatopulmonary syndrome rat pulmonary microvascular hyperplasia.

Hepatopulmonary syndrome (HPS) is a triad of advanced liver disease, intrapulmonary vasodilatation and arterial hypoxemia. Increasing evidence shows that HPS is associated with pulmonary microvascular hyperplasia. The aim of this work was to investigate the underlying mechanism of miR-145 in regulating the proliferation of pulmonary microvascular endothelial cells (PMVECs) and angiogenesis in HPS via plasminogen activator inhibitor-1 (PAI-1). To test this, morphology score and number of pulmonary microvascular were assessed in lung tissues from rats with HPS by Hematoxylin and Eosin (H&E) staining. Expression levels of PAI-1 were assessed in lung tissues from HPS rats, as well as in PMVECs treated with HPS rat serum. We also selected the putative microRNA binding site on PAI-1 by bioinformatics analysis. Then, miR145-3p and miR145-5p expression levels in the lungs and PMVECs of rats were detected by qRT-PCR because miR145-5p is a microRNA binding site on PAI-1. In addition, the effects of miR-145-5p regulation on PAI-1 were examined by upregulation and downregulation of miR-145-5p and specific lentivirus transfection was used to overexpress and knockdown PAI-1 to assess PAI-1 function on PMVECs proliferation. Our data showed that levels of PAI-1 expression in lung tissue of rats increased significantly when rats were treated with common bile duct ligation. We found that levels of miR-145-5p were frequently downregulated in HPS tissues and cell lines, and overexpression of miR-145-5p dramatically inhibited PMVECs proliferation. We further verified PAI-1 as a novel and direct target of miR-145-5p in HPS. MiR-145-5p inhibits PAI-1 synthesis and the expression changes of PAI-1 directly affect the proliferation of PMVECs. We concluded that miR-145-5p negatively regulates PMVEC proliferation through PAI-1 expression. In addition, overexpression of miR-145-5p may prove beneficial as a therapeutic strategy for HPS treatment.

Acute right ventricular failure after orthotopic liver transplantation.

The interdependence between the heart and liver in maintaining hemodynamic stability during the perioperative period of either orthotopic heart (OHT) or liver (OLT) transplantation is important. The pre-transplant hemodynamic changes that occur in patients with end-stage liver disease (ESLD) can include decreased systemic vascular resistance, poor ventricular response to stress and increased cardiac output (CO). Concomitant pulmonary disorders are often present in ESLD. Portopulmonary hypertension (PoPHTN) is an important marker for increased mortality in liver transplant patients. The pathophysiologic mechanisms specific to PoPHTN have been compared with other known forms of pulmonary hypertension, including primary pulmonary hypertension, and has been found to fall within a spectrum of disorders related to factors both due to intrinsic liver failure [with resultant portal hypertension and hepatopulmonary syndrome (HPS)] as well as pulmonary vascular remodeling. We present a 47-year-old Caucasian female with ESLD secondary to non-alcoholic steatohepatitis and HPS. Our current case demonstrates the difficulty in managing patients with acute pulmonary hypertension after OLT. Review of the contemporary literature demonstrated a total of eight case reports of post-transplant severe pulmonary hypertension thought to be due to a combination of either HPS or PoPHTN. This case highlights the complexities of patient management in the acute setting after OLT. Furthermore, it demonstrates the intricate role of careful preoperative evaluation and screening in patients undergoing workup for solid organ transplantation.