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

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.

Aberrant cGMP signaling persists during recovery in mice with oxygen-induced pulmonary hypertension

“…One group has demonstrated in mice that septal thickness is unchanged after 14d of exposure to 85% O 2 , but is modestly increased after 14d of room air recovery [ 21 ], whereas another group using >90% O 2 , showed an increase in septal thickness after 10d of exposure [ 33 ]. In rats, some groups have seen increased septal thickness with 100% O 2 , but others have not with 60% O 2 [ 34 , 35 ]. Thus, there is some variability in hyperoxia-induced changes in septal thickness that seems dose dependent.…”

Aberrant Pulmonary Vascular Growth and Remodeling in Bronchopulmonary Dysplasia

“…For example, in the thoracic aorta, LPA causes NOS-dependent vasodilation by acting through the LPA receptor-1 (LPAR1). Mice containing mutations in the LPAR1 demonstrate decreased lung inflammation and fibrosis and improved survival in an experimental model of BPD, and pharmacologic blockade of the LPAR-1 and -3 protects against pathologic vascular remodeling, limiting muscularization and RVH in newborn rats exposed to chronic hyperoxia ( 116 ). Although there were some phenotypic differences between the mice with genetic deletions of LPAR-1 and pharmacologic blockade that require future study, these studies suggest that the LPA pathway may prove to be a promising new target for BPD.…”

Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

“…Several LPAR1 antagonists have been used for in vivo fibrosis treatments (Ki16425 [37], VPC-32183 [38], and AM966 [39]). LPAR1 deficiency attenuates pulmonary injury by reducing pulmonary inflammation and fibrosis [40]. LPAR1 knockdown was reported to inhibit human mesenchymal stem cell migration to reduce fibrosis [41].…”