Inflammation Gets on the Lung's Nerves: IL-17 and Neuroendocrine Cells Mediate Ozone Responses in Obesity.
Inflammation Gets on the Lung's Nerves: IL-17 and Neuroendocrine Cells Mediate Ozone Responses in Obesity.
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炎症影响肺部神经：IL-17 和神经内分泌细胞介导肥胖中的臭氧反应。
DOI：
10.1165/rcmb.2017-0363ed
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发表时间：
2018
影响因子：
6.4
通讯作者：
Tighe,RobertM
中科院分区：
文献类型：
--
作者：
Garantziotis,Stavros;Tighe,RobertM
大多数肺部疾病是由环境暴露与宿主生物学相互作用引起的。因此，可以合理地假设，慢性肺病（例如哮喘）患病率的增加可能是由于日益普遍的环境暴露（例如通过人类活动和气候变化）与改变的人类生物学（例如通过饮食引起的肥胖）相互作用所致。臭氧是肺部疾病恶化的重要触发因素。进行良好的流行病学研究表明，臭氧每年导致约 800 人死亡、4,500 人住院，并且。 100 万个限制活动日，仅在美国就花费了 50 亿美元 (1, 2)。美国环境保护署表示，由于气候变化，臭氧的水平和影响将大幅增加(3)。与此同时，肥胖已成为一种全球流行病，并且显然与肺部生理学的变化和对损伤的反应有关 (4)。这两个重大公共卫生问题之间的潜在重叠促使研究人员探索肥胖对臭氧引起的肺部炎症和气道高反应性（AHR）的影响。 Mathews 及其同事在本期杂志上进行的研究（第 341-351 页）建立在这一不断扩展的研究基础上 (5)。作者首先观察到臭氧暴露和肥胖都会增加肺部 IL-17A 水平，IL-17A 是一种与哮喘发病机制密切相关的细胞因子 (6)。他们在小鼠中观察到，肥胖（基因引起的和饮食引起的）在臭氧暴露后放大了 IL-17 的诱导，并且 IL-17 在臭氧暴露后观察到的肥胖引起的中性粒细胞增多和 AHR 增加中占了很大一部分。此外，他们还发现胃泌素释放肽（Grp）（气道神经内分泌细胞的产物）是 IL-17 下游肥胖放大、臭氧诱导的肺损伤的重要贡献者。臭氧暴露后，肥胖小鼠肺组织中的 Grp 及其受体 Grpr 均增加，导致中性粒细胞增多和 AHR 增加。尽管 IL-17A 阻断并没有降低 Grpr 水平，但它确实降低了 Grpr 的表达。Mathews 及其同事提供的数据开辟了令人兴奋的研究途径。 IL-17A 现在被认为是哮喘发病机制的重要驱动因素，特别是在严重的、难治性的病例中 (6)。认识到内源性（即肥胖）和外源性（即臭氧暴露）因素在肺部协同诱导IL-17，提出了这些因素是否影响IL-17为主的哮喘内型的发展和建立的问题。此外，我们还可能询问其他环境暴露或医疗状况是否会导致哮喘内型恶化。我们还可以在哮喘治疗的精准医学方法中考虑这些因素：也许患有哮喘和 IL-17 的患者
Most lung diseases result from the interaction of environmental exposures with host biology. It is therefore logical to assume that the increasing prevalence of chronic lung diseases, such as asthma, may be due to increasingly pervasive environmental exposures (eg, through human activity and climate change) interacting with altered human biology (eg, through diet-induced obesity). Ozone is an important trigger of lung disease exacerbations. Well-conducted epidemiological studies have suggested that ozone leads annually to approximately 800 deaths, 4,500 hospitalizations, and. 1 million restricted-activity days, at a cost of $5 billion (1, 2), in the United States alone. The US Environmental Protection Agency stated that due to climate change, the levels and effects of ozone will increase substantially (3). Concurrently, obesity has become a global epidemic and is clearly associated with changes in lung physiology and responses to injuries (4). The potential overlap between these two significant public health concerns has led researchers to explore the effects of obesity in ozone-induced lung inflammation and airway hyperresponsiveness (AHR). The study in this issue of the Journal by Mathews and colleagues (pp. 341-351) builds upon this expanding body of research (5). The authors started from the observation that both ozone exposure and obesity increase lung levels of IL-17A, a cytokine that is strongly implicated in the pathogenesis of asthma (6). They observed in mice that obesity (both gene-and dietinduced) amplified IL-17 induction after ozone exposure, and that IL-17 accounted for a significant part of the obesity-induced increase in neutrophilia and AHR observed after ozone exposure. Furthermore, they identified gastrin-releasing peptide (Grp), a product of airway neuroendocrine cells, as an important contributor to obesity-amplified, ozone-induced lung injury downstream of IL-17. Both Grp and its receptor Grpr were increased in lung tissue of obese mice after ozone exposure, and contributed to the increased neutrophilia and AHR. Although IL-17A blockade did not decrease Grp levels, it did decrease expression of Grpr.The data presented by Mathews and colleagues open up exciting research avenues. IL-17A is now recognized as an important driver of asthma pathogenesis, particularly in severe, treatmentresistant cases (6). The recognition that both endogenous (ie, obesity) and exogenous (ie, ozone exposure) factors synergistically induce IL-17 in the lung raises the question as to whether these factors influence the development and establishment of an IL-17-predominant asthma endotype. In addition, we may also ask whether other environmental exposures or medical conditions contribute to exacerbated asthma endotypes. We may also consider such factors in a precision-medicine approach to asthma treatment: perhaps patients with asthma and the IL-17