Abstract：
Few pharmacological interventions are able to improve the mortality rate of acute lung injury and acute respiratory distress syndrome (ALI/ARDS). The aim of this research was to elucidate whether endoplasmic reticulum (ER) stress and c‑Jun‑N‑terminal kinase (JNK)‑mitochondria pathways serve important roles in ALI/ARDS and to determine whether the key component Sab is a potential treatment target. The current study investigated the activation of ER stress and the JNK pathway, the content of JNK located on the mitochondria during ER stress and lipopolysaccharide (LPS)‑induced ALI/ARDS by western blot analysis. The treatment effects of Tat‑SabKIM1, a selective inhibitor of JNK located on mitochondria were explored by multiple methods including histopathological evaluation, lung cell apoptosis tested by TUNEL assay, mitochondrial membrane permeability and survival analysis. The results verified that ER stress was enhanced during LPS‑induced ALI/ARDS and could induce activation of the JNK pathway and JNK‑mitochondrial localization as well as mitochondrial dysfunction and cell death. Tat‑SabKIM1 alleviated LPS injection‑induced lung injury and improved mouse survival rates by specifically inhibiting JNK localization to mitochondria and mito‑JNK signal activation without affecting cytosolic/nuclear JNK activation. The protective effect of Tat‑SabKIM1 against ALI/ARDS was partly caused by inhibition of the excessive activation of mitochondria‑mediated apoptosis and autophagy. These results showed the important role of Sab as a treatment target of ALI/ARDS and the potential treatment effect of Tat‑SabKIM1. In conclusion, abnormal activation of the JNK‑mitochondrial pathway could significantly disrupt the normal physiological function of lung cells, resulting in the occurrence of ALI/ARDS and selective inhibit of JNK located on mitochondria by Tat‑SabKIM1 had a protective effect against the mitochondrial dysfunction and cell death caused by endoplasmic reticulum stress in mice with LPS‑induced ALI/ARDS.
摘要：
很少有药物干预措施能够提高急性肺损伤和急性呼吸窘迫综合征（ALI/ARDS）的死亡率。这项研究的目的是阐明内质网（ER）应激和c-Jun-N-末端激酶（JNK）-线粒体途径是否在ALI/ARDS中起重要作用，并确定关键成分Sab是否是潜在的治疗目标。当前的研究调查了ER应激的激活和JNK途径，通过蛋白质印迹分析，在ER应激和脂多糖（LPS）诱导的ALI/ARDS期间位于线粒体上的JNK含量。通过包括组织病理学评估在内的多种方法探索了位于线粒体上的JNK的选择性抑制剂Tat-SabKIM1的治疗效果。通过TUNEL测定法检测肺细胞凋亡，线粒体膜通透性和存活分析。结果证实，在LPS诱导的ALI/ARDS过程中，ER应激增强，并可诱导JNK途径和JNK线粒体定位以及线粒体功能障碍和细胞死亡的激活。Tat‑SabKIM1通过特异性抑制JNK定位于线粒体和mito‑JNK信号激活而不影响胞浆/核JNK激活，减轻了LPS注射诱导的肺损伤并提高了小鼠存活率。Tat-SabKIM1对ALI/ARDS的保护作用部分是由抑制线粒体介导的细胞凋亡和自噬的过度激活引起的。这些结果显示了Sab作为ALI/ARDS治疗靶点的重要作用以及Tat-SabKIM1的潜在治疗效果。总之,JNK线粒体途径的异常激活可以显著破坏肺细胞的正常生理功能，导致ALI/ARDS的发生和Tat-SabKIM1选择性抑制线粒体上的JNK对LPS诱导的ALI/ARDS小鼠内质网应激引起的线粒体功能障碍和细胞死亡具有保护作用。
