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STATE-OF-THE-ART PAPER

Inflammation, Growth Factors, and Pulmonary Vascular Remodeling

Paul M. Hassoun, MD^_*,_*, Luc Mouthon, MD, PhD, Joan A. Barberà, MD, Saadia Eddahibi, PhD, Sonia C. Flores, PhD^||, Friedrich Grimminger, MD, PhD^¶, Peter Lloyd Jones, PhD^#, Michael L. Maitland, MD, PhD^_**, Evangelos D. Michelakis, MD, Nicholas W. Morrell, MA, MD, John H. Newman, MD, Marlene Rabinovitch, MD^||||, Ralph Schermuly, PhD^¶¶, Kurt R. Stenmark, MD^##, Norbert F. Voelkel, MD^_***, Jason X.-J. Yuan, MD, PhD and Marc Humbert, MD, PhD

^_* Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
Department of Internal Medicine, Cochin Hospital, Paris-Descartes University, Paris, France
Servei de Pneumologia, Hospital Clinic, Universitat de Barcelona, and CIBERES, Barcelona, Spain
Departement de Physiologie, Hôpital Henri Mondor, Créteil, France
^|| Division of Pulmonary Sciences & Critical Care Medicine, University of Colorado, Denver, Colorado
^¶ Medical Clinic IV and V, University Hospital Giessen and Marburg GmbH, Giessen, Germany
^# University of Pennsylvania, Penn/CMREF Center for Pulmonary Arterial Hypertension Research, Philadelphia, Pennsylvania
^_** Section of Hematology/Oncology, Department of Medicine and Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, Illinois
Pulmonary Hypertension Program, University of Alberta Hospital, Edmonton, Alberta, Canada
Pulmonary Vascular Diseases Unit, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom
Department of Medicine, Division of Pulmonary/Allergy/Immunology, Vanderbilt University Medical Center, Nashville, Tennessee
^|||| The Wall Center for Pulmonary Vascular Diseases, Stanford University School of Medicine, Stanford, California
^¶¶ Department of Internal Medicine, Justus-Liebig University of Giessen, Giessen, Germany
^## Developmental Lung Biology Laboratory, University of Colorado at Denver and Health Sciences Center, Denver, Colorado
^_*** Pulmonary and Critical Care Division, Virginia Commonwealth University, Richmond, Virginia
Department of Medicine, University of California San Diego, La Jolla, California
Université Paris-Sud, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, Clamart, France

Manuscript received February 6, 2009; accepted April 15, 2009.

^_* Reprint requests and correspondence: Dr. Paul M. Hassoun, Professor of Medicine, Johns Hopkins University Department of Medicine, Pulmonary and Critical Care Medicine, 1830 East Monument Street, Room 530, Baltimore, Maryland 21287 (Email: phassoun{at}jhmi.edu).

Inflammatory processes are prominent in various types of human and experimental pulmonary hypertension (PH) and are increasingly recognized as major pathogenic components of pulmonary vascular remodeling. Macrophages, T and B lymphocytes, and dendritic cells are present in the vascular lesions of PH, whether in idiopathic pulmonary arterial hypertension (PAH) or PAH related to more classical forms of inflammatory syndromes such as connective tissue diseases, human immunodeficiency virus (HIV), or other viral etiologies. Similarly, the presence of circulating chemokines and cytokines, viral protein components (e.g., HIV-1 Nef), and increased expression of growth (such as vascular endothelial growth factor and platelet-derived growth factor) and transcriptional (e.g., nuclear factor of activated T cells or NFAT) factors in these patients are thought to contribute directly to further recruitment of inflammatory cells and proliferation of smooth muscle and endothelial cells. Other processes, such as mitochondrial and ion channel dysregulation, seem to convey a state of cellular resistance to apoptosis; this has recently emerged as a necessary event in the pathogenesis of pulmonary vascular remodeling. Thus, the recognition of complex inflammatory disturbances in the vascular remodeling process offers potential specific targets for therapy and has recently led to clinical trials investigating, for example, the use of tyrosine kinase inhibitors. This paper provides an overview of specific inflammatory pathways involving cells, chemokines and cytokines, cellular dysfunctions, growth factors, and viral proteins, highlighting their potential role in pulmonary vascular remodeling and the possibility of future targeted therapy.

Key Words: growth factors • inflammation • pulmonary vascular remodeling

Abbreviations and Acronyms   AECA = anti-endothelial cell antibody   bcl = B-cell lymphoma   COPD = chronic obstructive pulmonary disease   EC = endothelial cell   EGF = epidermal growth factor   ET = endothelin   HCV = hepatitis C virus   HHV = human herpes virus   HIV = human immunodeficiency virus   5-HT = serotonin   5-HTT = serotonin transporter   IL = interleukin   IPAH = idiopathic pulmonary arterial hypertension   Kv = voltage-dependent potassium channel   MCT = monocrotaline   mRNA = messenger ribonucleic acid   NFAT = nuclear factor of activated T cells   PA = pulmonary artery   PAH = pulmonary arterial hypertension   PCR = polymerase chain reaction   PDGF = platelet-derived growth factor   PDGFR = platelet-derived growth factor receptor   PH = pulmonary hypertension   RV = right ventricular   SIV = simian immunodeficiency virus   SMC = smooth muscle cell   SSc = systemic sclerosis   TGF = transforming growth factor   TN = tenascin   TNF = tumor necrosis factor   VEGF = vascular endothelial growth factor

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