Pleiotropic effects of interleukin-6 in a "two-hit" murine model of acute respiratory distress syndrome
Pleiotropic effects of interleukin-6 in a "two-hit" murine model of acute respiratory distress syndrome
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DOI：
10.1086/675991
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发表时间：
2014-06-01
影响因子：
2.6
通讯作者：
Garcia, Joe G. N.
中科院分区：
文献类型：
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作者：
Goldman, Julia L.;Sammani, Saad;Garcia, Joe G. N.
急性呼吸窘迫综合征（ARDS）患者的白细胞介素-6（IL-6）水平升高，与发病率和死亡率增加相关。IL-6在ARDS中的确切作用已被证明难以研究，因为它在肺损伤的小鼠模型中表现出促炎或抗炎作用，这取决于所使用的模型。为了提高对这种复杂细胞因子在ARDS中的作用的理解，我们在IL-6（-/-）小鼠中使用脂多糖（LPS）和呼吸机诱导的肺损伤（VILI）的临床相关组合来评估IL-6。对支气管肺泡灌洗液（BAL）、全肺组织和组织学进行了损伤炎症标志物的评价。采用跨内皮电阻法评价IL-6对体外培养的内皮细胞的作用。在野生型小鼠中，与单独的LPS或VILI相比，组合模型显示肺损伤显著增加。IL-6（-/-）小鼠显示出BAL细胞炎症的统计学显著性降低以及肺损伤的组织学评分降低，仅在联合模型中观察到变化。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提供了对血管渗漏的保护。然而，体外数据显示，当IL-6与其可溶性受体结合时，实际上引起内皮细胞通透性的显著增加，这表明在体内观察到的保护可能是由于IL-6和其他炎症介质的复杂相互作用，而不是IL-6的直接作用。这些研究表明，双重损伤模型在评估IL-6在ARDS中对炎性细胞和肺内皮的多效性作用方面具有实用性。
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.