Adult Lysophosphatidic Acid Receptor 1-Deficient Rats with Hyperoxia-Induced Neonatal Chronic Lung Disease Are Protected against Lipopolysaccharide-Induced Acute Lung Injury

Abstract

Aim: Survivors of neonatal chronic lung disease or bronchopulmonary dysplasia (BPD) suffer from compromised lung function and are at high risk for developing lung injury by multiple insults later in life. Because neonatal lysophosphatidic acid receptor-1 (LPAR1)-deficient rats are protected against hyperoxia-induced lung injury, we hypothesize that LPAR1-deficiency may protect adult survivors of BPD from a second hit response against lipopolysaccharides (LPS)-induced lung injury. Methods: Directly after birth, Wistar control and LPAR1-deficient rat pups were exposed to hyperoxia (90%) for 8 days followed by recovery in room air. After 7 weeks, male rats received either LPS (2 mg kg −1 ) or 0.9% NaCl by intraperitoneal injection. Alveolar development and lung inflammation were investigated by morphometric analysis, IL-6 production, and mRNA expression of cytokines, chemokines, coagulation factors, and an indicator of oxidative stress. Results: LPAR1-deficient and control rats developed hyperoxia-induced neonatal emphysema, which persisted into adulthood, as demonstrated by alveolar enlargement and decreased vessel density. LPAR1-deficiency protected against LPS-induced lung injury. Adult controls with BPD exhibited an exacerbated response toward LPS with an increased expression of pro-inflammatory mRNAs, whereas LPAR1-deficient rats with BPD were less sensitive to this “second hit” with a decreased pulmonary influx of macrophages and neutrophils, interleukin-6 (IL-6) production, and mRNA expression of IL-6, monocyte chemoattractant protein-1, cytokine-induced neutrophil chemoattractant 1, plasminogen activator inhibitor-1 , and tissue factor . Conclusion: LPAR1-deficient rats have increased hyperoxia-induced BPD survival rates and, despite the presence of neonatal emphysema, are less sensitive to an aggravated “second hit” than Wistar controls with BPD. Intervening in LPA-LPAR1-dependent signaling may not only have therapeutic potential for neonatal chronic lung disease, but may also protect adult survivors of BPD from sequelae later in life.

Expression profiling of genes regulated by sphingosine kinase1 signaling in a murine model of hyperoxia induced neonatal bronchopulmonary dysplasia

“…Delving further into lipid mediated signaling other than S1P, we noted a significant increase in gene expression of LPA receptor 3 in the WT HO (1.78 fold increase with FDR of 0.014869) which is in agreement with hyperoxia studies carried out in rat BPD models [ 50 ]. Related studies in humans and rats revealed increased protein expression of autotaxin, Lpar1 and Lpar3 that co-localized to airway epithelial cells following exposure to hyperoxia [ 51 ].…”

Lysophospholipids in Lung Inflammatory Diseases

“…In addition to changes in LPA and ATX, LPA receptor levels were increased in lung cells in both hyperoxia-and LPS-induced experimental acute lung injuries [79,81]. The studies using LPA receptor-deficient mice or antagonists provided solid data to support that LPA receptors, especially LPA 1 , act as proinflammatory GPCRs during the progression of hyperoxia-or LPSinduced acute lung injury and sepsis [79,88,89]. Interestingly, LPA 1 seems to have no effects on alveolar-capillary integrity as no changes of LPSinduced BAL protein were detected in LPA 1deficient mice or ki16425-treated mice [79].…”

Long noncoding RNA ZFAS1 promotes tumorigenesis and metastasis in nasopharyngeal carcinoma by sponging miR‐892b to up‐regulate LPAR1 expression

“…27,28 Recent studies have found that LPAR1 is a carcinogenic factor and able to enhance metastasis and invasion in several cancers, such as melanoma, breast cancer and ovarian cancer. Here, we identified that the downstream effector of miR-892b is lysophosphatidic acid receptor 1 (LPAR1).…”