Pulmonary arterial hypertension (PAH) is the major cause of death in fast growing meat-type chickens (broiler chickens). At present, the underlying mechanisms that give rise to PAH are not fully understood. To identify the metabonomics profiles characterizing the process, we conducted a comprehensive gas chromatography-mass spectrometry (GC-MS)-based metabolic profiling of lung tissues from PAH broilers and age-matched controls. PAH was induced by excess salt in drinking water. Medial hypertrophy of pulmonary arteries was present in PAH birds as compared with controls. The metabonomics profiles of lung tissues well distinguished PAH broilers from control subjects. Significant changes in the levels of 41 metabolites were detected in PAH vs normal birds. Aside from the metabolic alterations indicating a status of oxidative stress and inflammation, evidence of reduced cellular uptake of arginine due to increased lysine biosynthesis and of a shift of arginine metabolism to arginase pathway were observed. In addition, PAH birds showed increased biosynthesis of fatty acids, which may be associated with excessive proliferation of vascular cells during pulmonary vascular remodeling. Furthermore, we observed significant changes in pentose phosphate pathway and increased aminomalonic acid in PAH broilers. These results provide additional biochemical insights into the pathogenesis of the PAH. Our data may lead to the development of new strategies to control PAH in broilers.
Background Plexiform lesions, which have a dynamic appearance in structure and cellular composition, are the histological hallmark of severe pulmonary arterial hypertension in humans. The pathogenesis of the lesion development remains largely unknown, although it may be related to local inflammation and dysfunction in early progenitor endothelial cells (eEPCs). We tested the hypothesis that eEPCs contribute to the development of plexiform lesions by differentiating into macrophages in the setting of chronic inflammation. Methods The eEPC markers CD133 and VEGFR-2, macrophage lineage marker mannose receptor C-type 1 (MRC1), TNFα and nuclear factor erythroid 2-related factor 2 (Nrf2) in plexiform lesions in a broiler model were determined by immunohistochemistry. eEPCs derived from peripheral blood mononuclear cells were exposed to TNFα, and macrophage differentiation and angiogenic capacity of the cells were evaluated by phagocytotic and Matrigel plug assays, respectively. The role of Nrf2 in eEPC-to-macrophage transition as well as in MRC1 expression was also evaluated. Intratracheal installation of TNFα was conducted to determine the effect of local inflammation on the formation of plexiform lesions. Results Cells composed of the early lesions have a typical eEPC phenotype whereas those in more mature lesions display molecular and morphological characteristics of macrophages. Increased TNFα production in plexiform lesions was observed with lesion progression. In vitro studies showed that chronic TNFα challenge directed eEPCs to macrophage differentiation accompanied by hyperactivation of Nrf2, a stress-responsive transcription factor. Nrf2 activation (Keap1 knockdown) caused a marked downregulation in CD133 but upregulation in MRC1 mRNA. Dual luciferase reporter assay demonstrated that Nrf2 binds to the promoter of MRC1 to trigger its expression. In good agreement with the in vitro observation, TNFα exposure induced macrophage differentiation of eEPCs in Matrigel plugs, resulting in reduced neovascularization of the plugs. Intratracheal installation of TNFα resulted in a significant increase in plexiform lesion density. Conclusions This work provides evidence suggesting that macrophage differentiation of eEPCs resulting from chronic inflammatory stimulation contributes to the development of plexiform lesions. Given the key role of Nrf2 in the phenotypic switching of eEPCs to macrophages, targeting this molecular might be beneficial for intervention of plexiform lesions.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.