BMP9/10 in Pulmonary Vascular Complications of Liver Disease.
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ABSTRACT:
SUBMITTER: Rochon ER
PROVIDER: S-EPMC7301744 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatopulmonary syndrome and portopulmonary hypertension are two pulmonary vascular complications of liver disease. The pathophysiology underlying each disorder is distinct, but patients with either condition may be limited by dyspnea. A careful evaluation of concomitant symptoms, the physical examination, pulmonary function testing and arterial blood gas analysis, and echocardiographic, imaging, and hemodynamic studies is crucial to establishing (and distinguishing) these diagnoses. Our understanding of the pathobiology, natural history, and treatment of these disorders has advanced considerably over the past decade; however, the presence of either still increases the risk of morbidity and mortality in patients with underlying liver disease. There is no effective medical treatment for hepatopulmonary syndrome. Although liver transplantation can resolve hepatopulmonary syndrome, there appears to be worse survival even with transplantation. Liver transplantation poses a very high risk of death in those with significant portopulmonary hypertension, where targeted medical therapies may improve functional status and allow successful transplantation in a small number of select patients.
| S-EPMC3570657 | biostudies-literature
Project description:Background and aimsPortopulmonary hypertension (POPH) was previously associated with a single-nucleotide polymorphism (SNP) rs7175922 in aromatase (cytochrome P450 family 19 subfamily A member 1 [CYP19A1]). We sought to determine whether genetic variants and metabolites in the estrogen signaling pathway are associated with POPH.Approach and resultsWe performed a multicenter case-control study. POPH patients had mean pulmonary artery pressure >25 mm Hg, pulmonary vascular resistance >240 dyn-sec/cm-5 , and pulmonary artery wedge pressure ≤15 mm Hg without another cause of pulmonary hypertension. Controls had advanced liver disease, right ventricular (RV) systolic pressure <40 mm Hg, and normal RV function by echocardiography. We genotyped three SNPs in CYP19A1 and CYP1B1 using TaqMan and imputed SNPs in estrogen receptor 1 using genome-wide markers. Estrogen metabolites were measured in blood and urine samples. There were 37 patients with POPH and 290 controls. Mean age was 57 years, and 36% were female. The risk allele A in rs7175922 (CYP19A1) was significantly associated with higher levels of estradiol (P = 0.02) and an increased risk of POPH (odds ratio [OR], 2.36; 95% confidence interval [CI], 1.12-4.91; P = 0.02) whereas other SNPs were not. Lower urinary 2-hydroxyestrogen/16-α-hydroxyestrone (OR per 1-ln decrease = 2.04; 95% CI, 1.16-3.57; P = 0.01), lower plasma levels of dehydroepiandrosterone-sulfate (OR per 1-ln decrease = 2.38; 95% CI, 1.56-3.85; P < 0.001), and higher plasma levels of 16-α-hydroxyestradiol (OR per 1-ln increase = 2.16; 95% CI, 1.61-2.98; P < 0.001) were associated with POPH.ConclusionsGenetic variation in aromatase and changes in estrogen metabolites were associated with POPH.
| S-EPMC8115214 | biostudies-literature
Project description:Inactivation of BMP9/10 in mice leads to attenuated contractility of smooth muscle cells and decreased blood pressure.Treatment of de-differentiated PASMCs with BMP9/10 resulted in a strong increase of ACTA2 expression as measured by immunofluorescence and RT-PCR, indicating a switch from the de-differentiated, synthetic to a differentiated, contractile state. To further study the role of BMP9/10 in smooth muscle cells, we isolate PSAMCs and stimulate cells with or without BMP9/10 and perform the RNA-seq analysis.
2020-05-31 | GSE147376 | GEO
Project description:BackgroundBMP9, originating from the liver, and BMP10 are circulating BMPs that preserve vascular endothelial integrity. We assessed BMP9, BMP10 and soluble endoglin (sEng) levels and their relationships to liver disease severity and associated pulmonary vascular syndromes in a cohort of well-characterised liver disease patients.MethodsPlasma samples from patients with liver disease (n = 83) and non-disease controls (n = 21) were assayed for BMP9, BMP10 and sEng. Levels were also assessed in a separate cohort of controls (n = 27) and PoPH patients (n = 8). Expression of mRNA and immunohistochemical staining was undertaken in liver biopsy specimens. Plasma BMP activity was assessed using an endothelial cell bioassay.FindingsPlasma BMP9 and BMP10 levels were normal in patients with compensated cirrhosis or fibrosis without cirrhosis, but markedly reduced in patients with decompensated cirrhosis, including those with hepatopulmonary syndrome (HPS) or portopulmonary hypertension (PoPH). Liver biopsy specimens revealed reduced mRNA expression and immunostaining for these ligands. Patient plasma samples with reduced BMP9 and BMP10 levels exhibited low BMP activity that was restored with exogenous BMP9. Endoglin mRNA expression was increased in cirrhotic livers and elevated circulating sEng levels in PoPH and HPS patients suggested increased endothelial sEng shedding in these syndromes.InterpretationPlasma BMP9 and BMP10 levels are reduced in decompensated cirrhosis, leading to reduced circulating BMP activity on the vascular endothelium. The pulmonary complications of cirrhosis, PoPH and HPS, are associated with markedly reduced BMP9 and BMP10 and increased sEng levels, suggesting that supplementation with exogenous ligands might be a therapeutic approach for PoPH and HPS.
| S-EPMC7248419 | biostudies-literature
Project description:The experiment monitors the response of human umbilical vein endothelial cells to stimulation with BMP9 and BMP10
2021-02-05 | GSE160023 | GEO
Project description:Sickle cell disease (SCD) is a common monogenetic disorder with high associated morbidity and mortality. The pulmonary complications of SCD are of particular importance, as acute chest syndrome and pulmonary hypertension have the highest associated mortality rates within this population. This article reviews the pathophysiology, diagnosis, and treatment of clinically significant pulmonary manifestations of SCD, including acute chest syndrome, asthma, and pulmonary hypertension in adult and pediatric patients. Clinicians should be vigilant in screening and treating such comorbidities to improve patient outcomes.
| S-EPMC3373067 | biostudies-literature
Project description:BackgroundBecause of the growing number of obese patients undergoing liver transplantation (LT), it is important to investigate the impact of obesity on post-transplant outcomes. Vascular complications are rare, but serious causes of morbidity and mortality after LT. It is not known if pre-transplant obesity is associated with an increased incidence of post-LT vascular complications.MethodsMedline, Embase, and Cochrane Library databases were searched in September 2017. The primary outcome was the impact of obesity on the vascular complication rate in adult LT recipients. Survival and biliary complications rates were also analyzed. Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated to compare pooled data between groups with a body mass index (BMI) ≥ 30 kg/m2 and < 30 kg/m2.ResultsSix retrospective cohort studies with a total of 987 patients with a BMI ≥ 30 kg/m2 (high BMI group) and 2911 patients with a BMI < 3 0 kg/m2 (control group) were included in the analysis. All studies had Newcastle-Ottawa Scale scores ≥4. The vascular complication rates were similar between the high BMI group and control group (RR = 1.13, 95% CI: 0.87-1.47, P = 0.27), as were the patient survival, graft survival, and biliary complication rates. In subgroup analysis, there was no difference in the vascular complication rates between BMI ≥ 35 vs. BMI < 25 kg/m2; BMI 30-35 vs. BMI 18-25 kg/m2; BMI ≥ 30 vs. BMI 18-25 kg/m2; and BMI ≥ 35 vs. BMI < 35 kg/m2. No difference was found in subgroup analysis when BMI was adjusted for ascites. However, recipients whose primary disease was alcoholic liver disease, those with a BMI ≥ 30 kg/m2 had higher incidence of vascular complications than those with a BMI < 30 kg/m2 (RR = 1.55, 95% CI: 1.07-2.25, P = 0.02) .ConclusionsBMI does not affect incidence of vascular complications after LT. High pre-transplant BMI is not a risk factor for patient survival and biliary complications after LT.
| S-EPMC6407261 | biostudies-literature
Project description:BackgroundClinical factors predicting pulmonary complications after lung resection have been well described, whereas the role of genetics is unknown. The vascular endothelial growth factor (VEGF) signaling pathway has been linked to acute lung injury. We hypothesized that genetic variations in this pathway may be associated with postoperative pulmonary complications after lung resection.MethodsOne hundred ninety-six single nucleotide polymorphisms (SNPs) in 17 genes in the VEGF pathway were genotyped in a discovery set of 264 patients and a replication set of 264 patients who underwent lobectomy for lung cancer. Multivariable analysis adjusting for baseline clinical factors was used to identify SNPs associated with pulmonary complications. Cumulative and classification and regression tree (CART) analyses were used to further stratify risk groups.ResultsThe overall number of pulmonary complications was 164/528 (31%). The effects of 6 SNPs were consistent in the discovery and replication sets (pooled p value<0.05). The rs9319425 SNP in the VEGF receptor gene FLT1 resulted in a 1.50-fold increased risk (1.15-1.96; p=0.003). A cumulative effect for the number of risk genotypes and complications was also evident (p<0.01). Patients carrying 5 risk genotypes had a 5.76-fold increase in risk (2.73-12.16; p=4.44×10(-6)). Regression tree analysis identified potential gene-gene interactions between FLT1:rs9319425 and RAF1:rs713178. The addition of the 6 SNPs to the clinical model increased the area under the receiver operating characteristic curve by 6.8%.ConclusionsGenetic variations in the VEGF pathway are associated with risk of pulmonary complications after lobectomy. This may offer insight into the underlying biological mechanisms of pulmonary complications.
| S-EPMC3466075 | biostudies-literature
Project description:Chronic obstructive pulmonary disease (COPD) is one of the most important causes of death worldwide, and in addition to its impact on the patient's health, it poses a major socioeconomic burden. Tobacco smoke, indoor cooking, and air pollution are major triggers of the disease. This article summarizes evidence for the concept that lung microvascular molecular alterations can be a driver of lung emphysema. If findings from preclinical models allow a transfer to the human situation, this concept can offer new approaches for curative treatment of lung emphysema.
| S-EPMC6944394 | biostudies-literature
Project description:BackgroundIn patients with end stage liver disease (ESLD) scheduled for liver transplantation (LT), an intraoperative incidental finding of elevated mean pulmonary arterial pressure (mPAP) may be observed. Its association with patient outcome has not been evaluated. We aimed to estimate the effects of an incidental finding of a mPAP > 20 mmHg during LT on the incidence of pulmonary complications.MethodsWe examined all patients who underwent a LT at Paul-Brousse hospital between January 1,2015 and December 31,2020. Those who received: a LT due to acute liver failure, a combined transplantation, or a retransplantation were excluded, as well as patients for whom known porto-pulmonary hypertension was treated before the LT or patients who underwent a LT for other etiologies than ESLD. Using right sided pulmonary artery catheterization measurements made following anesthesia induction, the study cohort was divided into two groups using a mPAP cutoff of 20 mmHg. The primary outcome was a composite of pulmonary complications. Univariate and multivariable logistic regression analyses were performed to identify variables associated with the primary outcome. Sensitivity analyses of multivariable models were also conducted with other mPAP cutoffs (mPAP ≥ 25 mmHg and ≥ 35 mmHg) and even with mPAP as a continuous variable.ResultsOf 942 patients who underwent a LT, 659 met our inclusion criteria. Among them, 446 patients (67.7%) presented with an elevated mPAP (mPAP of 26.4 ± 5.9 mmHg). When adjusted for confounding factors, an elevated mPAP was not associated with a higher risk of pulmonary complications (adjusted OR: 1.16; 95%CI 0.8-1.7), nor with 90 days-mortality or any other complications. In our sensitivity analyses, we observed a lower prevalence of elevated mPAP when increasing thresholds (235 patients (35.7%) had an elevated mPAP when defined as ≥ 25 mmHg and 41 patients (6.2%) had an elevated mPAP when defined as ≥ 35 mmHg). We did not observe consistent association between a mPAP ≥ 25 mmHg or a mPAP ≥ 35 mmHg and our outcomes.ConclusionIncidental finding of elevated mPAP was highly prevalent during LT, but it was not associated with a higher risk of postoperative complications.
| S-EPMC9490933 | biostudies-literature