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Pleiotropic effects of interleukin-6 in a two-hit murine model of acute respiratory distress syndrome

机译:白细胞介素6在急性呼吸窘迫综合征两次打击小鼠模型中的多效性作用

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摘要

Patients with acute respiratory distress syndrome (ARDS) exhibit elevated levels of interleukin-6 (IL-6), which correlate with increased morbidity and mortality. The exact role of IL-6 in ARDS has proven difficult to study because it exhibits either pro- or anti-inflammatory actions in mouse models of lung injury, depending on the model utilized. In order to improve understanding of the role of this complex cytokine in ARDS, we evaluated IL-6 using the clinically relevant combination of lipopolysaccharide (LPS) and ventilator-induced lung injury (VILI) in IL-6−/− mice. Bronchoalveolar lavage fluid (BAL), whole-lung tissue, and histology were evaluated for inflammatory markers of injury. Transendothelial electrical resistance was used to evaluate the action of IL-6 on endothelial cells in vitro. In wild-type mice, the combination model showed a significant increase in lung injury compared to either LPS or VILI alone. IL-6−/− mice exhibited a statistically significant decrease in BAL cellular inflammation as well as lower histologic scores for lung injury, changes observed only in the combination model. A paradoxical increase in BAL total protein was observed in IL-6−/− mice exposed to LPS, suggesting that IL-6 provides protection from vascular leakage. However, in vitro data showed that IL-6, when combined with its soluble receptor, actually caused a significant increase in endothelial cell permeability, suggesting that the protection seen in vivo was likely due to complex interactions of IL-6 and other inflammatory mediators rather than to direct effects of IL-6. These studies suggest that a dual-injury model exhibits utility in evaluating the pleiotropic effects of IL-6 in ARDS on inflammatory cells and lung endothelium.
机译:患有急性呼吸窘迫综合征(ARDS)的患者的白介素6(IL-6)水平升高,这与发病率和死亡率增加相关。已证明很难研究IL-6在ARDS中的确切作用,因为根据所使用的模型,它在肺损伤的小鼠模型中表现出促炎或抗炎作用。为了增进对这种复杂细胞因子在ARDS中作用的理解,我们使用脂多糖(LPS)和呼吸机诱发的肺损伤(VILI)的临床相关组合评估了IL-6,IL-6 -/-< / sup>小鼠。评估了支气管肺泡灌洗液(BAL),整个肺组织和组织学的损伤性炎症标志物。使用内皮电阻评估IL-6对体外内皮细胞的作用。在野生型小鼠中,与单独使用LPS或VILI相比,组合模型显示出肺损伤的显着增加。 IL-6 -/-小鼠的BAL细胞炎症表现出统计学上的显着降低,并且肺损伤的组织学评分更低,只有在联合模型中才能观察到这种变化。在暴露于LPS的IL-6 -/-小鼠中观察到BAL总蛋白的反常增加,表明IL-6提供了防止血管渗漏的保护作用。但是,体外数据显示,IL-6与可溶性受体结合后,实际上会引起内皮细胞通透性的显着提高,这表明体内观察到的保护作用可能是由于IL-6与其他炎症介质的复杂相互作用所致。而不是直接影响IL-6。这些研究表明,双损伤模型在评估ARDS中IL-6对炎症细胞和肺内皮的多效性方面具有实用性。

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