Adult Lysophosphatidic Acid Receptor 1-Deficient Rats with Hyperoxia-Induced Neonatal Chronic Lung Disease Are Protected against Lipopolysaccharide-Induced Acute Lung Injury.
Adult Lysophosphatidic Acid Receptor 1-Deficient Rats with Hyperoxia-Induced Neonatal Chronic Lung Disease Are Protected against Lipopolysaccharide-Induced Acute Lung Injury.
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DOI：
10.3389/fphys.2017.00155
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发表时间：
2017
影响因子：
4
通讯作者：
Wagenaar GT
中科院分区：
文献类型：
--
作者：
Chen X;Walther FJ;Laghmani EH;Hoogeboom AM;Hogen-Esch AC;van Ark I;Folkerts G;Wagenaar GT
目的：新生儿慢性肺病或支气管肺发育不良(BPD)的存活者肺功能受损，在以后的生活中有发生多次肺损伤的高风险。由于新生溶血磷脂酸受体-1(LPAR1)缺陷大鼠对高氧诱导的肺损伤具有保护作用，我们推测LPAR1缺陷可能保护成年BPD幸存者免受内毒素(LPS)诱导的肺损伤的二次打击反应。方法：Wistar对照组和LPAR1基因缺陷大鼠出生后立即暴露于高氧(90%)中8d，然后在室内空气中恢复。7周后，雄性大鼠腹腔注射脂多糖(2 mg kg−-1)或0.9%生理盐水。通过形态计量学分析、IL-6产生以及细胞因子、趋化因子、凝血因子和氧化应激指标的mRNA表达来研究肺泡发育和肺部炎症。结果：LPAR1基因缺陷大鼠和对照组大鼠出现高氧诱导的新生儿肺气肿，并持续到成年，表现为肺泡增大和血管密度降低。LPAR1缺乏对内毒素诱导的肺损伤具有保护作用。患有BPD的成年对照组表现出对内毒素的反应加剧，促炎症的mRNAs表达增加，而BPD的LPAR1缺陷大鼠对这种二次打击不那么敏感，巨噬细胞和中性粒细胞的肺内流入减少，IL-6(IL-6)产生减少，IL-6、单核细胞趋化蛋白-1、细胞因子诱导的中性粒细胞趋化因子1、纤溶酶原激活物抑制物-1和组织因子的mRNA表达减少。结论：LPAR1基因缺陷的大鼠增加了高氧诱导的BPD存活率，尽管存在新生儿肺气肿，但与患有BPD的Wistar对照组相比，对加重的“二次打击”不那么敏感。干预LPA-LPAR1依赖的信号转导可能不仅具有治疗新生儿慢性肺部疾病的潜力，还可能保护成年BPD幸存者在以后的生活中免受后遗症的影响。
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.