NADPH oxidase mediates synergistic effects of IL-17 and TNF-α on CXCL1 expression by epithelial cells after lung ischemia-reperfusion
NADPH oxidase mediates synergistic effects of IL-17 and TNF-α on CXCL1 expression by epithelial cells after lung ischemia-reperfusion
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DOI：
10.1152/ajplung.00205.2013
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发表时间：
2014-01-01
影响因子：
4.9
通讯作者：
Laubach, Victor E.
中科院分区：
文献类型：
--
作者：
Sharma, Ashish K.;Mulloy, Daniel P.;Laubach, Victor E.
缺血再灌注（I/R）损伤导致肺移植患者死亡率和发病率增加。肺I/R损伤包括先天免疫反应引起的炎症。来自iNKT细胞和肺泡巨噬细胞的IL-17和tnf - α分别对肺I/R损伤起重要作用。本研究验证了IL-17和tnf - α在肺I/R过程中通过NADPH氧化依赖机制协同介导肺泡II型上皮（ATII）细胞产生CXCL1（一种强效中性粒细胞趋化因子）的假设。使用肺门钳模型，野生型和p47(phox-/-) （NADPH氧化酶缺陷）小鼠进行左肺I/R，给予或不给予重组IL-17和/或tnf - α治疗。与单独使用IL-17或tnf - α治疗相比，IL-17和tnf - α联合治疗I/R的野生型小鼠显著增强了肺功能障碍、水肿、CXCL1的产生和中性粒细胞浸润。然而，p47（phox-/-）小鼠在I/R后肺功能障碍、CXCL1产生和肺损伤明显减少，而联合il -17- tnf - α治疗并未增强肺功能障碍。此外，在急性体外缺氧-再氧化模型中，与单独使用任何一种细胞因子相比，联合il -17- tnf - α处理小鼠ATII细胞显示出CXCL1表达的多倍协同增加，而NADPH氧化酶抑制剂显著减弱了CXCL1表达。缺氧-再氧化暴露的iNKT细胞和巨噬细胞（分别是IL-17和tnf - α的主要来源）向ATII细胞的条件培养基转移显著增强了CXCL1的产生，该过程被NADPH氧化酶抑制剂阻断。这些结果表明，IL-17和tnf - α通过NADPH氧化酶依赖机制协同介导I/R后ATII细胞产生CXCL1，诱导中性粒细胞浸润和肺I/R损伤。
Ischemia-reperfusion (I/R) injury leads to increased mortality and morbidity in lung transplant patients. Lung I/R injury involves inflammation contributed by innate immune responses. IL-17 and TNF-alpha, from iNKT cells and alveolar macrophages, respectively, contribute importantly to lung I/R injury. This study tests the hypothesis that IL-17 and TNF-alpha synergistically mediate CXCL1 (a potent neutrophil chemokine) production by alveolar type II epithelial (ATII) cells via an NADPH oxidasedependent mechanism during lung I/R. Using a hilar clamp model, wild-type and p47(phox-/-) (NADPH oxidase-deficient) mice underwent left lung I/R, with or without recombinant IL-17 and/or TNF-alpha treatment. Wild-type mice undergoing I/R treated with combined IL-17 and TNF-alpha had significantly enhanced lung dysfunction, edema, CXCL1 production, and neutrophil infiltration compared with treatment with IL-17 or TNF-alpha alone. However, p47(phox-/-) mice had significantly less pulmonary dysfunction, CXCL1 production, and lung injury after I/R that was not enhanced by combined IL-17-TNF-alpha treatment. Moreover, in an acute in vitro hypoxia-reoxygenation model, murine ATII cells showed a multifold synergistic increase in CXCL1 expression after combined IL-17-TNF-alpha treatment compared with treatment with either cytokine alone, which was significantly attenuated by an NADPH oxidase inhibitor. Conditioned media transfer from hypoxia-reoxygenation-exposed iNKT cells and macrophages, major sources of IL-17 and TNF-alpha, respectively, to ATII cells significantly enhanced CXCL1 production, which was blocked by NADPH oxidase inhibitor. These results demonstrate that IL-17 and TNF-alpha synergistically mediate CXCL1 production by ATII cells after I/R, via an NADPH oxidase-dependent mechanism, to induce neutrophil infiltration and lung I/R injury.