Role of second-hand smoke (SHS)-induced proteostasis/autophagy impairment in pediatric lung diseases.
Role of second-hand smoke (SHS)-induced proteostasis/autophagy impairment in pediatric lung diseases.
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DOI：
10.1186/s40348-017-0069-7
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发表时间：
2017-12
期刊：
影响因子：
--
通讯作者：
Vij N
中科院分区：
文献类型：
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作者：
Patel N;Trumph CD;Bodas M;Vij N
暴露于二手烟草烟雾（SHS）是慢性肺部疾病发展的主要风险因素之一。怀孕期间吸烟可能导致新生儿的出生缺陷，包括肺功能障碍，增加对机会性病原体的易感性，或引发儿童呼吸系统表现，如支气管肺发育不良（BPD）。此外，儿童早期暴露于SHS可能对肺部健康产生负面影响，尽管确切的机制尚不清楚。自噬是香烟烟雾（CS）调节成人肺中重要的蛋白质抑制机制。在这里，我们试图调查SHS暴露是否会损害小儿肺部的自噬。将妊娠的C57 BL/6小鼠暴露于室内空气或SHS中14天。随后将新生幼仔暴露于室内空气或SHS（5小时/天）1或14天，并收获肺。对从小儿小鼠肺中分离的可溶性和不溶性蛋白组分进行免疫印迹，以检测泛素（Ub）、p62、VCP、HIF-1α和β-肌动蛋白。我们的数据显示，短期暴露于SHS（1或14天）导致蛋白质稳态和自噬损伤，如通过在儿科小鼠肺的不溶性蛋白质级分中的泛素化蛋白（Ub）、p62（受损自噬标记物）和含valosin蛋白（VCP）的积累的显著增加所证明的。此外，暴露于SHS的小鼠肺中HIF-1α水平的增加指向了儿科人群中SHS诱导的肺部疾病起始的新机制。为了验证体内研究，我们证明了用蛋白酶体抑制剂（MG-132）处理人支气管上皮细胞（Beas 2b细胞）诱导HIF-1α表达，其通过与自噬诱导药物半胱胺共同处理来控制。SHS暴露诱导的蛋白质稳态/自噬损伤可介导儿科受试者慢性肺部疾病的发生。因此，我们的数据证明了蛋白质抑制/自噬诱导药物（如半胱胺）作为SHS诱导的儿科肺部疾病的潜在治疗干预策略的评估。
Exposure to second-hand tobacco smoke (SHS) is one of the prime risk factors for chronic lung disease development. Smoking during pregnancy may lead to birth defects in the newborn that include pulmonary dysfunction, increased susceptibility to opportunistic pathogens, or initiation of childhood respiratory manifestations such as bronchopulmonary dysplasia (BPD). Moreover, exposure to SHS in early childhood can have negative impact on lung health, although the exact mechanisms are unclear. Autophagy is a crucial proteostatic mechanism modulated by cigarette smoke (CS) in adult lungs. Here, we sought to investigate whether SHS exposure impairs autophagy in pediatric lungs. Pregnant C57BL/6 mice were exposed to room air or SHS for 14 days. The newborn pups were subsequently exposed to room air or SHS (5 h/day) for 1 or 14 days, and lungs were harvested. Soluble and insoluble protein fractions isolated from pediatric mice lungs were subjected to immunoblotting for ubiquitin (Ub), p62, VCP, HIF-1α, and β-actin. Our data shows that short-term exposure to SHS (1 or 14 days) leads to proteostasis and autophagy-impairment as evident by significant increase in accumulation of ubiquitinated proteins (Ub), p62 (impaired-autophagy marker) and valosin-containing protein (VCP) in the insoluble protein fractions of pediatric mice lungs. Moreover, increased HIF-1α levels in SHS-exposed mice lungs points towards a novel mechanism for SHS-induced lung disease initiation in the pediatric population. Validating the in vivo studies, we demonstrate that treatment of human bronchial epithelial cells (Beas2b cells) with the proteasome inhibitor (MG-132) induces HIF-1α expression that is controlled by co-treatment with autophagy-inducing drug, cysteamine. SHS-exposure induced proteostasis/autophagy impairment can mediate the initiation of chronic lung disease in pediatric subjects. Hence, our data warrants the evaluation of proteostasis/autophagy-inducing drugs, such as cysteamine, as a potential therapeutic intervention strategy for SHS-induced pediatric lung diseases.