Pulmonary arterial hypertension: bridging the present to the future.
Ontology highlight
ABSTRACT:
SUBMITTER: Humbert M
PROVIDER: S-EPMC9487232 | biostudies-literature | 2012 Dec
REPOSITORIES: biostudies-literature
Publications
Pulmonary arterial hypertension: bridging the present to the future.
Humbert Marc M Souza Rogerio R Galiè Nazzareno N McLaughlin Vallerie V Simonneau Gérald G Rubin Lewis L
European respiratory review : an official journal of the European Respiratory Society 20121201 126
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Project description:Approximately 8-42% of premature infants with chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD), develop pulmonary hypertension (PH). Infants with BPD-PH carry alarmingly high mortality rates of up to 47%. Effective PH-targeted pharmacotherapies are desperately needed for these infants. Although many PH-targeted pharmacotherapies are commonly used to treat BPD-PH, all current use is off-label. Moreover, all current recommendations for the use of any PH-targeted therapy in infants with BPD-PH are based on expert opinion and consensus statements. Randomized Control Trials (RCTs) are needed to determine the efficacy of PH-targeted treatments in premature infants with or at risk of BPD-PH. Prior to performing efficacy RCTs, studies need to be conducted to obtain pharmacokinetic, pharmacodynamic, and safety data for any pharmacotherapy used in this understudied and fragile patient population. This review will discuss current and needed treatment strategies, identify knowledge deficits, and delineate both challenges to be overcome and approaches to be taken to develop effective PH-targeted pharmacotherapies that will improve outcomes for premature infants with or at risk of developing BPD-PH.
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Project description:Although multiple gene and protein expression have been extensively profiled in human pulmonary arterial hypertension (PAH), the mechanism for the development and progression of pulmonary hypertension remains elusive. Analysis of the global metabolomic heterogeneity within the pulmonary vascular system leads to a better understanding of disease progression. Using a combination of high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung. The results suggest that PAH has specific metabolic pathways contributing to increased ATP synthesis for the vascular remodeling process in severe pulmonary hypertension. These identified metabolites may serve as potential biomarkers for the diagnosis of severe PAH. By profiling metabolomic alterations of the PAH lung, we reveal new pathogenic mechanisms of PAH in its later stage, which may differ from the earlier stage of PAH, opening an avenue of exploration for therapeutics that target metabolic pathway alterations in the progression of PAH. Global profiles were determined in human lung tissue and compared across 11 normal and 12 severe pulmonary arterial hypertension patients. Using a combination of microarray and high-throughput liquid-and-gas-chromatography-based mass spectrometry, we showed unbiased metabolomic profiles of disrupted glycolysis, increased TCA cycle, and fatty acid metabolites with altered oxidation pathways in the severe human PAH lung.
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Project description:Pulmonary arterial hypertension (PAH) is a disease of the lung blood vessels that results in right heart failure. PAH is thought to occur in about 5% to 10% of patients with hepatosplenic schistosomiasis, particularly due to S. mansoni. The lung blood vessel injury may result from a combination of embolization of eggs through portocaval shunts into the lungs causing localized Type 2 inflammatory response and vessel remodeling, triggering of autonomous pathology that becomes independent of the antigen, and high cardiac output as seen in portopulmonary hypertension. The condition is likely underdiagnosed as there is little systematic screening, and risk factors for developing PAH are not known. Screening is done by echocardiography, and formal diagnosis requires invasive right heart catheterization. Patients with Schistosoma-associated PAH show reduced functional capacity and can be treated with pulmonary vasodilators, which improves symptoms and may improve survival. There are animal models of this disease that might help in understanding disease pathogenesis and identify novel targets to screen and treatment. Pathogenic mechanisms include Type 2 immunity and activation and signaling in the TGF-β pathway. There are still major uncertainties regarding Schistosoma-associated PAH development, course and treatment.
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