title: Emergence of fibroblasts with a proinflammatory epigenetically altered phenotype in severe hypoxic pulmonary hypertension.
abstract: Persistent accumulation of monocytes/macrophages in the pulmonary artery adventitial/perivascular areas of animals and humans with pulmonary hypertension has been documented. The cellular mechanisms contributing to chronic inflammatory responses remain unclear. We hypothesized that perivascular inflammation is perpetuated by activated adventitial fibroblasts, which, through sustained production of proinflammatory cytokines/chemokines and adhesion molecules, induce accumulation, retention, and activation of monocytes/macrophages. We further hypothesized that this proinflammatory phenotype is the result of the abnormal activity of histone-modifying enzymes, specifically, class I histone deacetylases (HDACs). Pulmonary adventitial fibroblasts from chronically hypoxic hypertensive calves (termed PH-Fibs) expressed a constitutive and persistent proinflammatory phenotype defined by high expression of IL-1β, IL-6, CCL2(MCP-1), CXCL12(SDF-1), CCL5(RANTES), CCR7, CXCR4, GM-CSF, CD40, CD40L, and VCAM-1. The proinflammatory phenotype of PH-Fibs was associated with epigenetic alterations as demonstrated by increased activity of HDACs and the findings that class I HDAC inhibitors markedly decreased cytokine/chemokine mRNA expression levels in these cells. PH-Fibs induced increased adhesion of THP-1 monocytes and produced soluble factors that induced increased migration of THP-1 and murine bone marrow-derived macrophages as well as activated monocytes/macrophages to express proinflammatory cytokines and profibrogenic mediators (TIMP1 and type I collagen) at the transcriptional level. Class I HDAC inhibitors markedly reduced the ability of PH-Fibs to induce monocyte migration and proinflammatory activation. The emergence of a distinct adventitial fibroblast population with an epigenetically altered proinflammatory phenotype capable of recruiting, retaining, and activating monocytes/macrophages characterizes pulmonary hypertension-associated vascular remodeling and thus could contribute significantly to chronic inflammatory processes in the pulmonary artery wall.
authors.affiliation: Division of Critical Care Medicine, Department of Pediatrics, University of Colorado at Denver, Aurora, CO 80045, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.forename: Suzette R
authors.initials: SR
authors.lastname: Riddle
authors.forename: Maria G
authors.initials: MG
authors.lastname: Frid
authors.forename: Karim C
authors.initials: KC
authors.lastname: El Kasmi
authors.forename: Timothy A
authors.initials: TA
authors.lastname: McKinsey
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Sokol
authors.forename: Derek
authors.initials: D
authors.lastname: Strassheim
authors.forename: Barbara
authors.initials: B
authors.lastname: Meyrick
authors.forename: Michael E
authors.initials: ME
authors.lastname: Yeager
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Flockton
authors.forename: B Alexandre
authors.initials: BA
authors.lastname: McKeon
authors.forename: Douglas D
authors.initials: DD
authors.lastname: Lemon
authors.forename: Todd R
authors.initials: TR
authors.lastname: Horn
authors.forename: Adil
authors.initials: A
authors.lastname: Anwar
authors.forename: Carlos
authors.initials: C
authors.lastname: Barajas
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D002417:Cattle; D002448:Cell Adhesion; D002465:Cell Movement; D003238:Connective Tissue / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D044127:Epigenesis, Genetic; D005347:Fibroblasts / Q000276:immunology* / Q000378:metabolism; D005455:Fluorescent Antibody Technique; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism; D006976:Hypertension, Pulmonary / Q000276:immunology* / Q000378:metabolism; D000860:Hypoxia / Q000276:immunology / Q000378:metabolism; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D010641:Phenotype; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D016207:Cytokines; D006655:Histone Deacetylases