Inflammation, growth factors, and pulmonary vascular remodeling.
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.
Hassoun
Paul M
PM
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University, Baltimore, Maryland. Electronic address: phassoun@jhmi.edu.
Mouthon
Luc
L
Department of Internal Medicine, Cochin Hospital, Paris-Descartes University, Paris, France.
Barberà
Joan A
JA
Servei de Pneumologia, Hospital Clinic, Universitat de Barcelona, and CIBERES, Barcelona, Spain.
Eddahibi
Saadia
S
Departement de Physiologie, Hôpital Henri Mondor, Créteil, France.
Flores
Sonia C
SC
Division of Pulmonary Sciences & Critical Care Medicine, University of Colorado, Denver, Colorado.
Grimminger
Friedrich
F
Medical Clinic IV and V, University Hospital Giessen and Marburg GmbH, Giessen, Germany.
Jones
Peter Lloyd
PL
University of Pennsylvania, Penn/CMREF Center for Pulmonary Arterial Hypertension Research, Philadelphia, Pennsylvania.
Maitland
Michael L
ML
Section of Hematology/Oncology, Department of Medicine and Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, Chicago, Illinois.
Michelakis
Evangelos D
ED
Pulmonary Hypertension Program, University of Alberta Hospital, Edmonton, Alberta, Canada.
Morrell
Nicholas W
NW
Pulmonary Vascular Diseases Unit, Department of Medicine, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.
Newman
John H
JH
Department of Medicine, Division of Pulmonary/Allergy/Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
Rabinovitch
Marlene
M
The Wall Center for Pulmonary Vascular Diseases, Stanford University School of Medicine, Stanford, California.
Schermuly
Ralph
R
Department of Internal Medicine, Justus-Liebig University of Giessen, Giessen, Germany.
Stenmark
Kurt R
KR
Developmental Lung Biology Laboratory, University of Colorado at Denver and Health Sciences Center, Denver, Colorado.
Voelkel
Norbert F
NF
Pulmonary and Critical Care Division, Virginia Commonwealth University, Richmond, Virginia.
Yuan
Jason X-J
JX
Department of Medicine, University of California San Diego, La Jolla, California.
Humbert
Marc
M
Université Paris-Sud, Service de Pneumologie et Réanimation Respiratoire, Hôpital Antoine Béclère, Clamart, France.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D018946:Chemokine CCL5; D020523:Chemokines, CX3C / Q000502:physiology; D016207:Cytokines / Q000502:physiology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology / Q000821:virology; D007249:Inflammation / Q000473:pathology / Q000503:physiopathology; D050778:NFATC Transcription Factors / Q000502:physiology; D012595:Scleroderma, Systemic / Q000473:pathology / Q000503:physiopathology; D014655:Vascular Resistance / Q000502:physiology
D000970:Antineoplastic Agents; D018946:Chemokine CCL5; D020523:Chemokines, CX3C; D016207:Cytokines; D050778:NFATC Transcription Factors