title: The role of inflammation in hypoxic pulmonary hypertension: from cellular mechanisms to clinical phenotypes.
abstract: Hypoxic pulmonary hypertension (PH) comprises a heterogeneous group of diseases sharing the common feature of chronic hypoxia-induced pulmonary vascular remodeling. The disease is usually characterized by mild to moderate pulmonary vascular remodeling that is largely thought to be reversible compared with the progressive irreversible disease seen in World Health Organization (WHO) group I disease. However, in these patients, the presence of PH significantly worsens morbidity and mortality. In addition, a small subset of patients with hypoxic PH develop "out-of-proportion" severe pulmonary hypertension characterized by pulmonary vascular remodeling that is irreversible and similar to that in WHO group I disease. In all cases of hypoxia-related vascular remodeling and PH, inflammation, particularly persistent inflammation, is thought to play a role. This review focuses on the effects of hypoxia on pulmonary vascular cells and the signaling pathways involved in the initiation and perpetuation of vascular inflammation, especially as they relate to vascular remodeling and transition to chronic irreversible PH. We hypothesize that the combination of hypoxia and local tissue factors/cytokines ("second hit") antagonizes tissue homeostatic cellular interactions between mesenchymal cells (fibroblasts and/or smooth muscle cells) and macrophages and arrests these cells in an epigenetically locked and permanently activated proremodeling and proinflammatory phenotype. This aberrant cellular cross-talk between mesenchymal cells and macrophages promotes transition to chronic nonresolving inflammation and vascular remodeling, perpetuating PH. A better understanding of these signaling pathways may lead to the development of specific therapeutic targets, as none are currently available for WHO group III disease.
authors.affiliation: Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado; steven.pugliese@ucdenver.edu.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Pugliese
authors.affiliation: Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Jens M
authors.initials: JM
authors.lastname: Poth
authors.affiliation: Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Mehdi A
authors.initials: MA
authors.lastname: Fini
authors.affiliation: Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; and.
authors.forename: Andrea
authors.initials: A
authors.lastname: Olschewski
authors.affiliation: Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of Colorado Denver, School of Medicine, Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Karim C
authors.initials: KC
authors.lastname: El Kasmi
authors.affiliation: Developmental Lung Biology, Cardiovascular Pulmonary Research Laboratories, Division of Pulmonary Sciences and Critical Care Medicine, Division of Pediatrics-Critical Care, Departments of Medicine and Pediatrics, University of Colorado, Anschutz Medical Campus, Aurora, Colorado;
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D044127:Epigenesis, Genetic / Q000276:immunology; D006801:Humans; D006976:Hypertension, Pulmonary / Q000276:immunology* / Q000378:metabolism; D008168:Lung / Q000098:blood supply / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology; D015398:Signal Transduction; D014657:Vasculitis / Q000276:immunology* / Q000378:metabolism
keywords: chronic nonresolving inflammation; fibroblasts; hypoxia; hypoxic pulmonary hypertension; inflammation; macrophages