Cellular and molecular pathobiology of pulmonary arterial hypertension
Marc Humbert, MD, PhD*,*,
Nicholas W. Morrell, MD ,
Stephen L. Archer, MD ,
Kurt R. Stenmark, MD ,
Margaret R. MacLean, Bsc, PhD||,
Irene M. Lang, MD¶,
Brian W. Christman, MD,
E. Kenneth Weir, MD**,
Oliver Eickelberg, MD ,
Norbert F. Voelkel, MD and
Marlene Rabinovitch, MD
* Service de Pneumologie et Réanimation Respiratoire, Centre des Maladies Vasculaires Pulmonaires, UPRES EA2705, Hôpital Antoine-Béclère, Université Paris-Sud, Clamart, France
Respiratory Medicine Unit, Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's Hospital, Cambridge, United Kingdom
Vascular Biology Group and Pulmonary Hypertension Program, Department of Medicine (Cardiology), University of Alberta, Edmonton, Alberta, Canada
Development Lung Biology Research, University of Colorado Health Sciences Center, Denver, Colorado, USA
|| Division of Biomedical and Life Sciences, Institute of Biomedical and Life Sciences, Glasgow University, Glasgow, United Kingdom
¶ Department of Cardiology, University of Vienna, Vienna, Austria
Center for Lung Research, Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA
** Department of Medicine, Veterans Affairs Medical Center, Minneapolis, Minnesota, USA
 Department of Internal Medicine, Justus-Liebig University, Giessen, Germany
 Pulmonary Hypertension Center, University of Colorado Health Sciences Center, Denver, Colorado, USA
 Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
Manuscript received January 7, 2004;
accepted February 3, 2004.
*
Reprint requests and correspondence: Dr. Marc Humbert, Service de Pneumologie, Hôpital Antoine-Béclère, 157, Rue de la Porte de Trivaux, 92140 Clamart, France. humbert{at}ipsc.u-psud.fr
Pulmonary arterial hypertension (PAH) has a multifactorial pathobiology. Vasoconstriction, remodeling of the pulmonary vessel wall, and thrombosis contribute to increased pulmonary vascular resistance in PAH. The process of pulmonary vascular remodeling involves all layers of the vessel wall and is complicated by cellular heterogeneity within each compartment of the pulmonary arterial wall. Indeed, each cell type (endothelial, smooth muscle, and fibroblast), as well as inflammatory cells and platelets, may play a significant role in PAH. Pulmonary vasoconstriction is believed to be an early component of the pulmonary hypertensive process. Excessive vasoconstriction has been related to abnormal function or expression of potassium channels and to endothelial dysfunction. Endothelial dysfunction leads to chronically impaired production of vasodilators such as nitric oxide and prostacyclin along with overexpression of vasoconstrictors such as endothelin (ET)-1. Many of these abnormalities not only elevate vascular tone and promote vascular remodeling but also represent logical pharmacological targets. Recent genetic and pathophysiologic studies have emphasized the relevance of several mediators in this condition, including prostacyclin, nitric oxide, ET-1, angiopoietin-1, serotonin, cytokines, chemokines, and members of the transforming-growth-factor-beta superfamily. Disordered proteolysis of the extracellular matrix is also evident in PAH. Future studies are required to find which if any of these abnormalities initiates PAH and which ones are best targeted to cure the disease.
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Abbreviations and Acronyms
| | BMP | = bone morphogenetic proteins | | ET | = endothelin | | 5-HT | = 5-hydroxytryptamine | | NO | = nitric oxide | | PAH | = pulmonary arterial hypertension | | TGF-ß | = transforming growth factor-beta | | TGF-ßR2 | = transforming growth factor-beta type-2 receptor | | VEGF | = vascular endothelial growth factor | | VIP | = vasoactive intestinal peptide |
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