title: Comparing the differential effects of LPA on the barrier function of human pulmonary endothelial cells.
abstract: Lysophosphatidic acid (LPA) is a class of bioactive lyso-phospholipid that mediates most of its biological effects through a family of G protein-coupled receptors of which six have been identified. The role of the LPA pathway in driving chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) has gained considerable academic and industry attention. Modulation of the pulmonary artery endothelial barrier function by the LPA1 receptor has been shown to drive pulmonary fibrosis in murine models of disease. The purpose of this study was (i) to assess the effect of LPA on the barrier function of human pulmonary arterial (HPAEC) and microvascular (HMVEC) endothelial cells and (ii) to identify the LPA receptor subtype(s) responsible for changes in human pulmonary endothelial cell permeability using LPA receptor antagonists and siRNA technology. Analysis of the LPA receptor subtype expression demonstrated predominant expression of LPA2 and LPA6 receptor subtypes in both HPAECs and HMVECs. HPAECs also exhibit low expression of LPA1, LPA3, and LPA4 receptor subtypes. Treatment of cells with increasing concentrations of LPA caused loss of barrier function in HPAECs but not HMVECs, despite both cell types exhibiting very similar LPA receptor expression profiles. The LPA-mediated loss of barrier function in HPAECs appears to be independent of the LPA1 receptor and likely to be mediated via the LPA6 receptor although we cannot exclude an additional role for the LPA2 and LPA4 receptors in mediating these effects. These results suggest cell-specific mechanisms exist in human pulmonary endothelial cells to permit regulation of barrier function downstream of LPA receptors. More importantly, our data indicate that selective LPA1 receptor antagonism may be insufficient for therapeutic use in pulmonary diseases where impaired endothelial barrier function is related to disease initiation and progression.
authors.affiliation: Inflammation Discovery Therapeutic Area, Hoffmann-La Roche Inc., Nutley, NJ 07110-1199, USA.
authors.forename: Yonglin
authors.initials: Y
authors.lastname: Ren
authors.forename: Liang
authors.initials: L
authors.lastname: Guo
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Tang
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Apparsundaram
authors.forename: Christopher
authors.initials: C
authors.lastname: Kitson
authors.forename: Jeremy
authors.initials: J
authors.lastname: Deguzman
authors.forename: Maria E
authors.initials: ME
authors.lastname: Fuentes
authors.forename: Luke
authors.initials: L
authors.lastname: Coyle
authors.forename: Rupal
authors.initials: R
authors.lastname: Majmudar
authors.forename: John
authors.initials: J
authors.lastname: Allard
authors.forename: Theresa
authors.initials: T
authors.lastname: Truitt
authors.forename: Rachid
authors.initials: R
authors.lastname: Hamid
authors.forename: Yun
authors.initials: Y
authors.lastname: Chen
authors.forename: Yimin
authors.initials: Y
authors.lastname: Qian
authors.forename: David C
authors.initials: DC
authors.lastname: Budd
mesh_terms: D001158:Arteries / Q000473:pathology; D002118:Calcium / Q000737:chemistry; D017931:DNA Primers / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000166:cytology*; D004727:Endothelium / Q000166:cytology; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000473:pathology; D008168:Lung / Q000166:cytology*; D008246:Lysophospholipids / Q000378:metabolism*; D008833:Microcirculation; D008856:Microscopy, Fluorescence / Q000379:methods; D010539:Permeability; D016133:Polymerase Chain Reaction / Q000379:methods; D034741:RNA, Small Interfering / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000378:metabolism; D013997:Time Factors
chemical_list: D017931:DNA Primers; C545560:LPAR6 protein, human; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid; D002118:Calcium