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-InWistar 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 Conflict of interestThe authors report no conflicts of interest to disclose. HHS Public Access Author Manuscript Author ManuscriptAuthor ManuscriptAuthor Manuscript 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.

Elevated potassium outward currents in hyperoxia treated atrial cardiomyocytes

“…Animal models for hyperoxia have been well‐established by many investigators in mice, rats, rabbits, guinea pigs, and hamsters, for various time periods (from 3 days up to 1 week) (Frank, Bucher, & Roberts, ; Groseclose & Frank, ; Johnston, Wright, Reed, & Finkelstein, ; Powers, Planck, Berger, Wall, & Rosenbaum, ). Much of these animal studies have been focused on investigating the effects of hyperoxia (both normobaric as well as hyperbaric) on acute lung injury, in neonates and in adults (Chen et al, , ; Howden et al, ; Matute‐Bello, Frevert, & Martin, ; Wagenaar et al, ). However, until recently, there are no published models concerning the impact of hyperoxia on cardiac injury/remodeling.…”