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 10days, 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.
Original language | English |
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Pages (from-to) | 358-375 |
Number of pages | 18 |
Journal | Acta Physiologica |
Volume | 216 |
Issue number | 3 |
DOIs | |
Publication status | Published - Mar 2016 |
Keywords
- bronchopulmonary dysplasia
- fibrosis
- lung inflammation
- lysophosphatidic acid receptor
- right ventricular hypertrophy
- PULMONARY ARTERIAL-HYPERTENSION
- BRONCHIAL EPITHELIAL-CELLS
- SPHINGOSINE 1-PHOSPHATE
- FIBROSIS
- INFLAMMATION
- EXPRESSION
- DISEASE
- HEART
- LPA
- ACTIVATION