Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5955001 | Chest | 2015 | 9 Pages |
Abstract
Pulmonary arterial hypertension (PAH) is a disorder in which mechanical obstruction of the pulmonary vascular bed is largely responsible for the rise in mean pulmonary arterial pressure, resulting in a progressive functional decline despite current available therapeutic options. The fundamental pathogenetic mechanisms underlying this disorder include pulmonary vasoconstriction, in situ thrombosis, medial hypertrophy, and intimal proliferation, leading to occlusion of the small to mid-sized pulmonary arterioles and the formation of plexiform lesions. Several predisposing or promoting mechanisms that contribute to excessive pulmonary vascular remodeling in PAH have emerged, such as altered crosstalk between cells within the vascular wall, sustained inflammation and dysimmunity, inhibition of cell death, and excessive activation of signaling pathways, in addition to the impact of systemic hormones, local growth factors, cytokines, transcription factors, and germline mutations. Although the spectrum of therapeutic options for PAH has expanded in the last 20 years, available therapies remain essentially palliative. However, over the past decade, a better understanding of new key regulators of this irreversible pulmonary vascular remodeling has been obtained. This review examines the state-of-the-art potential new targets for innovative research in PAH, focusing on (1) the crosstalk between cells within the pulmonary vascular wall, with particular attention to the role played by dysfunctional endothelial cells; (2) aberrant inflammatory and immune responses; (3) the abnormal extracellular matrix function; and (4) altered BMPRII/KCNK3 signaling systems. A better understanding of novel pathways and therapeutic targets will help in the designing of new and more effective approaches for PAH treatment.
Keywords
PGI25-HTRegulatory T lymphocyteMMPmPAPTregANGIIMCPPAHSMCTGFBMPRIIECMFGFAngiotensin IIendothelintransforming growth factorSerotoninSmooth muscle cellEndothelial cellMIFMigration inhibitory factorfibroblast growth factorPulmonary arterial hypertensionmean pulmonary arterial pressureExtracellular matrixmatrix metalloproteinaseMicroRNAMiRNANitric oxidePulmonary hypertensionmonocyte chemoattractant proteinprostacyclin
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Authors
Christophe PhD, Ly PhD, Barbara PhD, Nicolas PhD, Alice MD, PhD, David MD, PhD, Marc MD, PhD,