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Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia‐induced lung injury in neonatal rats
Author(s) -
Chen X.,
Walther F. J.,
Boxtel R.,
Laghmani E. H.,
Sengers R. M. A.,
Folkerts G.,
DeRuiter M. C.,
Cuppen E.,
Wagenaar G. T. M.
Publication year - 2016
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/apha.12622
Subject(s) - hyperoxia , lysophosphatidic acid , lung , receptor , chemistry , medicine , pharmacology
Aim Blocking of lysophosphatidic acid ( LPA ) receptor ( LPAR ) 1 may be a novel therapeutic option for bronchopulmonary dysplasia ( BPD ) by preventing the LPAR 1‐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 LPAR 1 deficiency in neonatal rats with a missense mutation in cytoplasmic helix 8 of LPAR 1 and of LPAR 1 and ‐3 blocking with Ki16425. Parameters investigated included survival, lung and heart histopathology, fibrin and collagen deposition, vascular leakage and differential m RNA expression in the lungs of key genes involved in LPA signalling and BPD pathogenesis. Results LPAR 1‐mutant rats were protected against experimental BPD and mortality with reduced alveolar septal thickness, lung inflammation (reduced influx of macrophages and neutrophils, and CINC 1 expression) and collagen III deposition. However, LPAR 1‐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 LPAR 1‐mutant rats, but did not reduce the pulmonary influx of neutrophils, CINC 1 expression and mortality in rats with experimental BPD . In addition, Ki16425 treatment protected against PAH and right ventricular hypertrophy. Conclusion LPAR 1 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 .