早年暴露于脂多糖可通过下调白细胞介素-13和JAK-STAT6信号通路预防卵清蛋白诱导的哮喘中的黏液高分泌。
LPS Exposure in Early Life Protects Against Mucus Hypersecretion in Ovalbumin-Induced Asthma by Down-Regulation of the IL-13 and JAK-STAT6 Pathways.
作者信息
Ding Fengxia, Liu Bo, Zou Wenjing, Tian Daiyin, Li Qubei, Dai Jihong, Luo Zhengxiu, Fu Zhou
机构信息
Department of Pediatric respiratory medicine, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorder, Chongqing, China International Science and Technology Cooperation base of Child development and Critical Disorders. Chongqing Key Laboratory of Child Infection and Immunity, Chongqing, China.
Department of Urology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorder, Chongqing, China.
出版信息
Cell Physiol Biochem. 2018;46(3):1263-1274. doi: 10.1159/000489109. Epub 2018 Apr 16.
BACKGROUND/AIMS: Previous studies have shown that lipopolysaccharide (LPS) exposure may have a protective effect on asthma by reducing airway hyper-responsiveness, airway inflammation and serum IgE levels. However, there are few studies investigating the effect of LPS on mucous secretion in asthma. In this study, we evaluate the relationship between LPS pre-treatment in infant mice and airway mucus hypersecretion in an OVA (ovalbumin)-induced asthma model, and further explore the mechanisms behind this effect.
METHODS
Mice were pre-treated with LPS by intranasal instillation (i.n.) from the 3rd day of life for 10 consecutive days before the OVA-induced asthma model was established. In order to detect mucus secretion, periodic acid-Schiff (PAS) staining was carried out, and the expression of Muc5ac was detected. The IL-13 levels in Bronchoalveolar lavage fluid (BALF) and lung tissue were also detected. In vitro, the expression of Muc5ac mRNA and protein was quantified in IL-13-stimulated 16HBE cells with or without LPS pre-treatment. In addition, proteins in the JAK2/STAT6 pathway, transcription factors (forkhead box transcription factor A2 (FOXA2), activation protein-1(AP-1), NF-κB), and the levels of reactive oxygen species (ROS) were also measured in vivo and in vitro.
RESULTS
LPS pre-treatment reduced mucus secretion, as demonstrated by decreased PAS staining and muc5ac expression. Further exploration of the underlying mechanisms of this phenomenon revealed that LPS pre-treatment decreased the production of IL-13, IL-13 induced ROS synthesis was reduced, and the JAK2/STAT6 pathway was inhibited. Decreased stat6 increased transcription factor FOXA2, and the relatively increased FOXA2 further decreased the level of Muc5ac and mucous hypersecretion in OVA-induced asthma.
CONCLUSIONS
LPS pre-treatment ameliorated mucus hypersecretion in an OVA-induced asthma model by inhibition of IL-13 production and by further inhibiting the JAK2/STAT6 pathway and ROS activity, and up-regulating expression of FOXA2.
背景/目的：先前的研究表明，暴露于脂多糖（LPS）可能通过降低气道高反应性、气道炎症和血清IgE水平对哮喘产生保护作用。然而，很少有研究调查LPS对哮喘中黏液分泌的影响。在本研究中，我们评估了幼鼠LPS预处理与卵清蛋白（OVA）诱导的哮喘模型中气道黏液高分泌之间的关系，并进一步探讨了这种作用背后的机制。
方法
在建立OVA诱导的哮喘模型之前，从出生第3天起，通过滴鼻（i.n.）连续10天对小鼠进行LPS预处理。为了检测黏液分泌，进行了过碘酸希夫（PAS）染色，并检测了Muc5ac的表达。还检测了支气管肺泡灌洗液（BALF）和肺组织中的IL-13水平。在体外，对有或没有LPS预处理的IL-13刺激的16HBE细胞中Muc5ac mRNA和蛋白的表达进行定量。此外，还在体内和体外测量了JAK2/STAT6途径中的蛋白、转录因子（叉头框转录因子A2（FOXA2）、活化蛋白-1（AP-1）、NF-κB）以及活性氧（ROS）水平。
结果
LPS预处理减少了黏液分泌，PAS染色和muc5ac表达降低证明了这一点。对这一现象潜在机制的进一步探索表明，LPS预处理降低了IL-13的产生，IL-13诱导的ROS合成减少，JAK2/STAT6途径受到抑制。Stat6减少使转录因子FOXA2增加，相对增加的FOXA2进一步降低了OVA诱导的哮喘中Muc5ac水平和黏液高分泌。
结论
LPS预处理通过抑制IL-13产生、进一步抑制JAK2/STAT6途径和ROS活性以及上调FOXA2表达，改善了OVA诱导的哮喘模型中的黏液高分泌。
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