Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats
2015; Wiley; Volume: 216; Issue: 3 Linguagem: Inglês
10.1111/apha.12622
ISSN1748-1716
AutoresXu Chen, Frans J. Walther, Ruben van Boxtel, El Houari Laghmani, Rozemarijn M. A. Sengers, Gert Folkerts, Marco C. DeRuiter, Edwin Cuppen, Gerry T. M. Wagenaar,
Tópico(s)Respiratory Support and Mechanisms
ResumoActa PhysiologicaVolume 216, Issue 3 p. 358-375 Original Article Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats X. Chen, X. Chen Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the NetherlandsSearch for more papers by this authorF. J. Walther, F. J. Walther Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USASearch for more papers by this authorR. van Boxtel, R. van Boxtel Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, Royal Netherlands Academy of Sciences and University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorE. H. Laghmani, E. H. Laghmani Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the NetherlandsSearch for more papers by this authorR. M. A. Sengers, R. M. A. Sengers Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the NetherlandsSearch for more papers by this authorG. Folkerts, G. Folkerts Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the NetherlandsSearch for more papers by this authorM. C. DeRuiter, M. C. DeRuiter Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the NetherlandsSearch for more papers by this authorE. Cuppen, E. Cuppen Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, Royal Netherlands Academy of Sciences and University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorG. T. M. Wagenaar, Corresponding Author G. T. M. Wagenaar Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands Correspondence: G. T. M. Wagenaar, PhD, Division of Neonatology, Department of Pediatrics, P3-P30, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands. E-mail: [email protected]Search for more papers by this author X. Chen, X. Chen Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the NetherlandsSearch for more papers by this authorF. J. Walther, F. J. Walther Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USASearch for more papers by this authorR. van Boxtel, R. van Boxtel Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, Royal Netherlands Academy of Sciences and University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorE. H. Laghmani, E. H. Laghmani Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the NetherlandsSearch for more papers by this authorR. M. A. Sengers, R. M. A. Sengers Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the NetherlandsSearch for more papers by this authorG. Folkerts, G. Folkerts Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the NetherlandsSearch for more papers by this authorM. C. DeRuiter, M. C. DeRuiter Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the NetherlandsSearch for more papers by this authorE. Cuppen, E. Cuppen Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, Royal Netherlands Academy of Sciences and University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorG. T. M. Wagenaar, Corresponding Author G. T. M. Wagenaar Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands Correspondence: G. T. M. Wagenaar, PhD, Division of Neonatology, Department of Pediatrics, P3-P30, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands. E-mail: [email protected]Search for more papers by this author First published: 23 October 2015 https://doi.org/10.1111/apha.12622Citations: 14Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinkedInRedditWechat Abstract Aim Blocking of lysophosphatidic acid (LPA) receptor (LPAR) 1 may be a novel therapeutic option for bronchopulmonary dysplasia (BPD) by preventing the LPAR1-mediated adverse effects of its ligand (LPA), consisting of lung inflammation, pulmonary arterial hypertension (PAH) and fibrosis. Methods In Wistar rats with experimental BPD, induced by continuous exposure to 100% oxygen for 10 days, we determined the beneficial effects of LPAR1 deficiency in neonatal rats with a missense mutation in cytoplasmic helix 8 of LPAR1 and of LPAR1 and -3 blocking with Ki16425. Parameters investigated included survival, lung and heart histopathology, fibrin and collagen deposition, vascular leakage and differential mRNA expression in the lungs of key genes involved in LPA signalling and BPD pathogenesis. Results LPAR1-mutant rats were protected against experimental BPD and mortality with reduced alveolar septal thickness, lung inflammation (reduced influx of macrophages and neutrophils, and CINC1 expression) and collagen III deposition. However, LPAR1-mutant rats were not protected against alveolar enlargement, increased medial wall thickness of small arterioles, fibrin deposition and vascular alveolar leakage. Treatment of experimental BPD with Ki16425 confirmed the data observed in LPAR1-mutant rats, but did not reduce the pulmonary influx of neutrophils, CINC1 expression and mortality in rats with experimental BPD. In addition, Ki16425 treatment protected against PAH and right ventricular hypertrophy. Conclusion LPAR1 deficiency attenuates pulmonary injury by reducing pulmonary inflammation and fibrosis, thereby reducing mortality, but does not affect alveolar and vascular development and, unlike Ki16425 treatment, does not prevent PAH in neonatal rats with experimental BPD. Supporting Information Filename Description apha12622-sup-0001-FigureS1.pptapplication/mspowerpoint, 763 KB Figure S1. Transfection efficiency is similar between wild-type and mutant LPAR1 expressing plasmids. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. 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