title: Leukotriene B4 Activates Pulmonary Artery Adventitial Fibroblasts in Pulmonary Hypertension.
abstract: A recent study demonstrated a significant role for leukotriene B4 (LTB4) causing pulmonary vascular remodeling in pulmonary arterial hypertension. LTB4 was found to directly injure luminal endothelial cells and promote growth of the smooth muscle cell layer of pulmonary arterioles. The purpose of this study was to determine the effects of LTB4 on the pulmonary adventitial layer, largely composed of fibroblasts. Here, we demonstrate that LTB4 enhanced human pulmonary artery adventitial fibroblast proliferation, migration, and differentiation in a dose-dependent manner through its cognate G-protein-coupled receptor, BLT1. LTB4 activated human pulmonary artery adventitial fibroblast by upregulating p38 mitogen-activated protein kinase as well as Nox4-signaling pathways. In an autoimmune model of pulmonary hypertension, inhibition of these pathways blocked perivascular inflammation, decreased Nox4 expression, reduced reactive oxygen species production, reversed arteriolar adventitial fibroblast activation, and attenuated pulmonary hypertension development. This study uncovers a novel mechanism by which LTB4 further promotes pulmonary arterial hypertension pathogenesis, beyond its established effects on endothelial and smooth muscle cells, by activating adventitial fibroblasts.
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, CA 94304.|Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Jin
authors.initials: J
authors.lastname: Qian
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, CA 94304.|Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Wen
authors.initials: W
authors.lastname: Tian
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, CA 94304.|Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Jiang
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, CA 94304.|Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Rasa
authors.initials: R
authors.lastname: Tamosiuniene
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, CA 94304.|Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Yon K
authors.initials: YK
authors.lastname: Sung
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, CA 94304.|Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Eric M
authors.initials: EM
authors.lastname: Shuffle
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, CA 94304.|Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Allen B
authors.initials: AB
authors.lastname: Tu
authors.affiliation: Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Antonia
authors.initials: A
authors.lastname: Valenzuela
authors.affiliation: Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Shirley
authors.initials: S
authors.lastname: Jiang
authors.affiliation: Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Roham T
authors.initials: RT
authors.lastname: Zamanian
authors.affiliation: Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: David F
authors.initials: DF
authors.lastname: Fiorentino
authors.affiliation: Virginia Commonwealth University, Richmond, VA 23284.
authors.forename: Norbert F
authors.initials: NF
authors.lastname: Voelkel
authors.affiliation: University of Michigan Health Systems, Ann Arbor, MI 48109.
authors.forename: Marc
authors.initials: M
authors.lastname: Peters-Golden
authors.affiliation: University of Colorado Denver, School of Medicine, Aurora, CO 80045.
authors.forename: Kurt R
authors.initials: KR
authors.lastname: Stenmark
authors.affiliation: Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Lorinda
authors.initials: L
authors.lastname: Chung
authors.affiliation: Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Marlene
authors.initials: M
authors.lastname: Rabinovitch
authors.affiliation: VA Palo Alto Health Care System, Palo Alto, CA 94304.|Stanford University, School of Medicine, Stanford, CA 94305.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Nicolls
mesh_terms: D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007093:Imidazoles / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism / Q000494:pharmacology*; D018613:Microscopy, Confocal; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000378:metabolism; D011651:Pulmonary Artery / Q000378:metabolism* / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D011923:Rats, Nude; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D018925:Chemokines; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011725:Pyridines; D014409:Tumor Necrosis Factor-alpha; D007975:Leukotriene B4; D001094:Arachidonate 5-Lipoxygenase; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580
keywords: NADPH oxidase; fibroblasts; inflammation; leukotriene B4; p38 mitogen-activated protein kinases; pulmonary artery; vascular remodeling