Extracellular ATP mediates the late phase of neutrophil recruitment to the lung in murine models of acute lung injury.
Extracellular ATP mediates the late phase of neutrophil recruitment to the lung in murine models of acute lung injury.
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在急性肺损伤的小鼠模型中，细胞外 ATP 介导中性粒细胞募集到肺部的后期。
DOI：
10.1152/ajplung.00229.2013
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Summer,Ross
中科院分区：
文献类型：
--
作者：
Shah,Dilip;Romero,Freddy;Stafstrom,William;Duong,Michelle;Summer,Ross
急性肺损伤(ALI)是一种严重的炎症状态，其发病机制与中性粒细胞向肺的迁移有着不可挽回的联系。中性粒细胞的激活和重新聚集到肺主要归因于局部产生的趋化因子。然而，我们对中性粒细胞重新聚集到肺中的大部分理解是基于对损伤开始后的早期时间点的研究。在这项研究中，我们试图评估气管内注射脂多糖或博莱霉素后，中性粒细胞趋化因子的表达与中性粒细胞流入肺之间的延长时间关系。在这两个模型中，结果显示中性粒细胞趋化因子的表达有两个阶段：第一个阶段，以高水平的CXCL1/角质形成细胞来源的趋化因子、CXCL2/单核细胞抑制蛋白-2和CXCL5/脂多糖诱导的趋化因子表达为特征；第二个阶段，以细胞外ATP的增加为特征。此外，我们还发现，无论是增强ATP分解代谢(ip ecto-5‘-核苷酸酶注射)还是抑制糖酵解ATP产生(ip 2-脱氧-d-葡萄糖治疗)的策略都能减少细胞外ATP的积累，限制血管渗漏，并有效地阻止中性粒细胞在内毒素滴注后向肺内募集中性粒细胞的晚期，而不是早期阶段。综上所述，本研究表明中性粒细胞向肺的募集是由趋化因子的时间依赖性表达所介导的，并提示减少细胞外ATP积聚的新策略可能会减弱ALI期间中性粒细胞的晚期募集并限制肺损伤。
Acute lung injury (ALI) is a severe inflammatory condition whose pathogenesis is irrevocably linked to neutrophil emigration to the lung. Activation and recruitment of neutrophils to the lung is mostly attributable to local production of the chemokines. However, much of our understanding of neutrophil recruitment to the lung is based on studies focusing on early time points after initiation of injury. In this study, we sought to evaluate the extended temporal relationship between neutrophil chemotactic factor expression and influx of neutrophils into the lung after intratracheal administration of either LPS or bleomycin. In both models, results demonstrated two phases of neutrophil chemotactic factor expression; first, an early phase characterized by high levels of CXCL1/keratinocyte-derived chemokine, CXCL2/monocyte-inhibitory protein-2, and CXCL5/LPS-induced chemokine expression, and second, a late phase distinguished by increases in extracellular ATP. Furthermore, we show that strategies aimed at either enhancing ATP catabolism (ip ecto-5′-nucleotidase administration) or inhibiting glycolytic ATP production (ip 2-deoxy-d-glucose treatment) reduce extracellular ATP accumulation, limit vascular leakage, and effectively block the late, but not the early, stages of neutrophil recruitment to the lung after LPS instillation. In conclusion, this study illustrates that neutrophil recruitment to the lung is mediated by the time-dependent expression of chemotactic factors and suggests that novel strategies, which reduce extracellular ATP accumulation, may attenuate late neutrophil recruitment and limit lung injury during ALI.