Pre-Treatment with Allopurinol or Uricase Attenuates Barrier Dysfunction but Not Inflammation during Murine Ventilator-Induced Lung Injury
Pre-Treatment with Allopurinol or Uricase Attenuates Barrier Dysfunction but Not Inflammation during Murine Ventilator-Induced Lung Injury
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DOI：
10.1371/journal.pone.0050559
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发表时间：
2012-11-30
期刊：
影响因子：
3.7
通讯作者：
Wieland, Catharina W.
中科院分区：
文献类型：
--
作者：
Kuipers, Maria T.;Aslami, Hamid;Wieland, Catharina W.
从损伤组织中释放的尿酸被认为是一种主要的内源性危险信号，尿酸晶体的局部灌注通过激活NLRP3炎性小体诱导急性肺部炎症。据报道，呼吸机诱导的肺损伤（VILI）是由NLRP3炎性体介导的，肺灌洗液中尿酸水平升高。我们研究了人肺损伤水平和尿酸在实验性VILI中的作用。方法：测定急性肺损伤（ALI）患者肺灌洗液尿酸水平。在另一组心脏手术患者中，尿酸水平与肺漏指数相关。在小鼠VILI模型中，研究了别嘌呤醇（抑制尿酸合成）和尿酸酶（降解尿酸）预处理对中性粒细胞内流、粘附分子上调、肺部和全身细胞因子水平、肺部病理以及参与尿酸识别的受体调节的影响。此外，测定肺灌洗液中总蛋白和免疫球蛋白M以及肺干湿比作为肺泡屏障功能障碍的标志物。结果：ALI患者尿酸水平升高。在心脏手术患者中，水平升高与肺漏指数显著相关。别嘌呤醇或尿酸酶治疗并没有减少呼吸机诱导的炎症、I κ b - α降解或NLRP3、toll样受体2和toll样受体4基因表达的上调。别嘌呤醇预处理小鼠肺泡屏障功能障碍减弱最为明显：两种治疗策略均降低了干湿比，别嘌呤醇还降低了总蛋白和免疫球蛋白M水平。结论：ALI患者局部尿酸水平升高。在小鼠中，别嘌呤醇和尿酸酶可减轻呼吸机诱导的肺泡屏障功能障碍。
Introduction: Uric acid released from injured tissue is considered a major endogenous danger signal and local instillation of uric acid crystals induces acute lung inflammation via activation of the NLRP3 inflammasome. Ventilator-induced lung injury (VILI) is mediated by the NLRP3 inflammasome and increased uric acid levels in lung lavage fluid are reported. We studied levels in human lung injury and the contribution of uric acid in experimental VILI.Methods: Uric acid levels in lung lavage fluid of patients with acute lung injury (ALI) were determined. In a different cohort of cardiac surgery patients, uric acid levels were correlated with pulmonary leakage index. In a mouse model of VILI the effect of allopurinol (inhibits uric acid synthesis) and uricase (degrades uric acid) pre-treatment on neutrophil influx, up-regulation of adhesion molecules, pulmonary and systemic cytokine levels, lung pathology, and regulation of receptors involved in the recognition of uric acid was studied. In addition, total protein and immunoglobulin M in lung lavage fluid and pulmonary wet/dry ratios were measured as markers of alveolar barrier dysfunction.Results: Uric acid levels increased in ALI patients. In cardiac surgery patients, elevated levels correlated significantly with the pulmonary leakage index. Allopurinol or uricase treatment did not reduce ventilator-induced inflammation, I kappa B-alpha degradation, or up-regulation of NLRP3, Toll-like receptor 2, and Toll-like receptor 4 gene expression in mice. Alveolar barrier dysfunction was attenuated which was most pronounced in mice pre-treated with allopurinol: both treatment strategies reduced wet/dry ratio, allopurinol also lowered total protein and immunoglobulin M levels.Conclusions: Local uric acid levels increase in patients with ALI. In mice, allopurinol and uricase attenuate ventilator-induced alveolar barrier dysfunction.