title: Relevant issues in the pathology and pathobiology of pulmonary hypertension.
abstract: Knowledge of the pathobiology of pulmonary hypertension (PH) continues to accelerate. However, fundamental gaps remain in our understanding of the underlying pathological changes in pulmonary arteries and veins in the different forms of this syndrome. Although PH primarily affects the arteries, venous disease is increasingly recognized as an important entity. Moreover, prognosis in PH is determined largely by the status of the right ventricle, rather than the levels of pulmonary artery pressures. It is increasingly clear that although vasospasm plays a role, PH is an obstructive lung panvasculopathy. Disordered metabolism and mitochondrial structure, inflammation, and dysregulation of growth factors lead to a proliferative, apoptosis-resistant state. These abnormalities may be acquired, genetically mediated as a result of mutations in bone morphogenetic protein receptor-2 or activin-like kinase-1, or epigenetically inherited (as a result of epigenetic silencing of genes such as superoxide dismutase-2). There is a pressing need to better understand how the pathobiology leads to severe disease in some patients versus mild PH in others. Recent recognition of a potential role of acquired abnormalities of mitochondrial metabolism in the right ventricular myocytes and pulmonary vascular cells suggests new therapeutic approaches, diagnostic modalities, and biomarkers. Finally, dissection of the role of pulmonary inflammation in the initiation and promotion of PH has revealed a complex yet fascinating interplay with pulmonary vascular remodeling, promising to lead to novel therapeutics and diagnostics. Emerging concepts are also relevant to the pathobiology of PH, including a role for bone marrow and circulating progenitor cells and microribonucleic acids. Continued interest in the interface of the genetic basis of PH and cellular and molecular pathogenetic links should further expand our understanding of the disease.
authors.affiliation: Program in Translational Lung Research, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado. Electronic address: rubin.tuder@ucdenver.edu.
authors.forename: Rubin M
authors.initials: RM
authors.lastname: Tuder
authors.affiliation: Department of Medicine, Queen's University, Kingston, Ontario, Canada.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Archer
authors.affiliation: Department of Pathology, Marie Lannelongue Hospital, University Paris-Sud, Le Plessis-Robinson, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.affiliation: Lerner Research Institute and Respiratory Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Serpil C
authors.initials: SC
authors.lastname: Erzurum
authors.affiliation: INSERM UMR 999, LabEx LERMIT, Marie Lannelongue Hospital and University Paris-Sud, School of Medicine, Kremlin-Bicêtre, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Guignabert
authors.affiliation: Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Evangelos
authors.initials: E
authors.lastname: Michelakis
authors.affiliation: Cardiovascular Institute and Department of Pediatrics and The Vera Moulton Wall Center for Pulmonary Vascular Disease, Stanford University School of Medicine, Stanford, California.
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
authors.affiliation: Excellence Cluster Cardio-Pulmonary System, German Lung Center, Universities of Giessen and Marburg Lung Center, Justus-Liebig-University, Giessen, Germany.
authors.forename: Ralph
authors.initials: R
authors.lastname: Schermuly
authors.affiliation: Cardiovascular Pulmonary Laboratory, Department of Pediatrics, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. Electronic address: nwm23@cam.ac.uk.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
mesh_terms: D000818:Animals; D006801:Humans; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology*; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology*; D011651:Pulmonary Artery / Q000378:metabolism / Q000473:pathology; D011667:Pulmonary Veins / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology
keywords: ALK; BMPR2; DC; ER; HIF; IPAH; LHF; PAH; PH; activin receptor-like kinase; bone morphogenetic protein type II receptor; dendritic cell; endoplasmic reticulum; hypoxia inducible factor; idiopathic pulmonary arterial hypertension; inflammation; left heart failure; metabolism; pulmonary arterial hypertension; pulmonary arteries; pulmonary hypertension; pulmonary veins