Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats.
OBJECTIVE
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.


CONCLUSIONS
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.
Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands.
X
X
Chen
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, USA.
F J
FJ
Walther
Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, Royal Netherlands Academy of Sciences and University Medical Center Utrecht, Utrecht, the Netherlands.
R
R
van Boxtel
Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands.
E H
EH
Laghmani
Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands.
R M A
RM
Sengers
Department of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands.
G
G
Folkerts
Department of Anatomy and Embryology, Leiden University Medical Center, Leiden, the Netherlands.
M C
MC
DeRuiter
Hubrecht Institute for Developmental Biology and Stem Cell Research, Cancer Genomics Center, Royal Netherlands Academy of Sciences and University Medical Center Utrecht, Utrecht, the Netherlands.
E
E
Cuppen
Division of Neonatology, Department of Pediatrics, Leiden University Medical Center, Leiden, the Netherlands.
G T M
GT
Wagenaar
D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001997:Bronchopulmonary Dysplasia / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D018496:Hyperoxia / Q000150:complications; D007555:Isoxazoles / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D051381:Rats; D011922:Rats, Mutant Strains; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors* / Q000172:deficiency*
C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D007555:Isoxazoles; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid
bronchopulmonary dysplasia; fibrosis; lung inflammation; lysophosphatidic acid receptor; right ventricular hypertrophy