Division of Pulmonary and Critical Care, Department of Internal Medicine, Tri-Service General Hospital, Taipei, Taiwan.
Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan.
Front Immunol. 2021 Aug 20;12:720844. doi: 10.3389/fimmu.2021.720844. eCollection 2021.
Ventilator-induced lung injury (VILI) is characterized by vascular barrier dysfunction and suppression of alveolar fluid clearance (AFC). Obesity itself leads to chronic inflammation, which may initiate an injurious cascade to the lungs and simultaneously induce a protective feedback. In this study, we investigated the protective mechanism of obesity on VILI in a mouse model.
The VILI model was set up 6-h mechanical ventilation with a high tidal volume. Parameters including lung injury score, STAT3/NFκB pathway, and AFC were assessed. Mice with diet-induced obesity were obtained by allowing free access to a high-fat diet since the age of 3 weeks. After a 9-week diet intervention, these mice were sacrificed at the age of 12 weeks. The manipulation of SOCS3 protein was achieved by siRNA knockdown and pharmaceutical stimulation using hesperetin. WNK4 knockin and knockout obese mice were used to clarify the pathway of AFC modulation.
Obesity itself attenuated VILI. Knockdown of SOCS3 in obese mice offset the protection against VILI afforded by obesity. Hesperetin stimulated SOCS3 upregulation in nonobese mice and provided protection against VILI. In obese mice, the WNK4 axis was upregulated at the baseline, but was significantly attenuated after VILI compared with nonobese mice. At the baseline, the manipulation of SOCS3 by siRNA and hesperetin also led to the corresponding alteration of WNK4, albeit to a lesser extent. After VILI, WNK4 expression correlated with STAT3/NFκB activation, regardless of SOCS3 status. Obese mice carrying WNK4 knockout had VILI with a severity similar to that of wild-type obese mice. The severity of VILI in WNK4-knockin obese mice was counteracted by obesity, similar to that of wild-type nonobese mice only.
Obesity protects lungs from VILI by upregulating SOCS3, thus suppressing the STAT3/NFκB inflammatory pathway and enhancing WNK4-related AFC. However, WNK4 activation is mainly from direct NFκB downstreaming, and less from SOCS3 upregulation. Moreover, JAK2-STAT3/NFκB signaling predominates the pathogenesis of VILI. Nevertheless, the interaction between SOCS3 and WNK4 in modulating VILI in obesity warrants further investigation.
呼吸机相关性肺损伤（VILI）的特征是血管屏障功能障碍和肺泡液体清除（AFC）抑制。肥胖本身会导致慢性炎症，这可能引发对肺部的损伤级联反应，并同时诱导保护性反馈。在这项研究中，我们在小鼠模型中研究了肥胖对 VILI 的保护机制。
使用大潮气量进行 6 小时机械通气来建立 VILI 模型。评估肺损伤评分、STAT3/NFκB 通路和 AFC 等参数。从 3 周龄开始，允许高脂肪饮食自由摄入，以获得饮食诱导肥胖的小鼠。经过 9 周的饮食干预后，这些小鼠在 12 周龄时被处死。通过 siRNA 敲低和使用桔皮素进行药物刺激来实现 SOCS3 蛋白的操作。使用 WNK4 基因敲入和基因敲除肥胖小鼠来阐明 AFC 调节途径。
肥胖本身减轻了 VILI。在肥胖小鼠中敲低 SOCS3 消除了肥胖对 VILI 的保护作用。桔皮素刺激非肥胖小鼠 SOCS3 的上调，并提供了对 VILI 的保护作用。在肥胖小鼠中，WNK4 轴在基线时上调，但与非肥胖小鼠相比，在 VILI 后明显减弱。在基线时，siRNA 和桔皮素对 SOCS3 的操作也导致了 WNK4 的相应改变，尽管程度较小。在 VILI 后，WNK4 的表达与 STAT3/NFκB 激活相关，无论 SOCS3 状态如何。携带 WNK4 基因敲除的肥胖小鼠的 VILI 严重程度与野生型肥胖小鼠相似。WNK4 基因敲入肥胖小鼠的 VILI 严重程度被肥胖所抵消，与野生型非肥胖小鼠相似。
肥胖通过上调 SOCS3 来保护肺部免受 VILI 的侵害，从而抑制 STAT3/NFκB 炎症通路并增强 WNK4 相关的 AFC。然而，WNK4 的激活主要来自 NFκB 的下游直接作用，而不是 SOCS3 的上调。此外，JAK2-STAT3/NFκB 信号通路在 VILI 的发病机制中占主导地位。然而，SOCS3 和 WNK4 在肥胖中调节 VILI 的相互作用仍需要进一步研究。
