Proinflammatory Cytokines Induce Bronchial Hyperplasia and Squamous Metaplasia in Smokers Implications for Chronic Obstructive Pulmonary Disease Therapy
Proinflammatory Cytokines Induce Bronchial Hyperplasia and Squamous Metaplasia in Smokers Implications for Chronic Obstructive Pulmonary Disease Therapy
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DOI：
10.1165/rcmb.2011-0353oc
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发表时间：
2012-07-01
影响因子：
6.4
通讯作者：
Delvenne, Philippe
中科院分区：
文献类型：
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作者：
Herfs, Michael;Hubert, Pascale;Delvenne, Philippe
气管-支气管鳞状化生在吸烟者中很常见，并与慢性阻塞性肺疾病(COPD)的呼吸道阻塞和肺癌风险增加有关。尽管这种可逆的上皮替代几乎总是与慢性炎症相关，但炎症介质在鳞状化生发病机制中的作用尚不清楚。在本研究中，我们研究了香烟烟雾介导的促炎细胞因子上调在气管、支气管上皮增生和鳞状化生的发生和治疗中的意义。应用免疫组织化学技术，我们发现吸烟者呼吸道上皮细胞较非吸烟者的正常纤毛上皮细胞表达更高的肿瘤坏死因子-α、IL-1β和IL-6，以及核因子-kappaB和激活蛋白-1/丝裂原活化蛋白激酶信号通路。此外，我们还证明了这些信号通路强烈影响体外培养的正常人呼吸道上皮细胞的增殖和分化状态。最后，我们将小鼠暴露在香烟烟雾中16周，并证明了抗TNF-α(依那西普)、抗IL-1β(Anakinra)和/或抗IL-6R(Tocilizumab)治疗显著减少了上皮增生和鳞状化生的发展。这些数据突出了可溶性炎性介质在气管、支气管鳞状化生发病机制中的重要性。因此，促炎细胞因子拮抗剂的应用可能在COPD患者的治疗中具有临床应用价值。
Tracheobronchial squamous metaplasia is common in smokers, and is associated with both airway obstruction in chronic obstructive pulmonary disease (COPD) and increased risk of lung cancer. Although this reversible epithelial replacement is almost always observed in association with chronic inflammation, the role of inflammatory mediators in the pathogenesis of squamous metaplasia remains unclear. In the present study, we investigated the implication of cigarette smoke-mediated proinflammatory cytokine up-regulation in the development and treatment of tracheobronchial epithelial hyperplasia and squamous metaplasia. Using immunohistological techniques, we showed a higher epithelial expression of TNF-alpha, IL-1 beta, and IL-6, as well as an activation of NF-kappa B and activator protein-1/mitogen-activated protein kinase signaling pathways in the respiratory tract of smoking patients, compared with the normal ciliated epithelium of nonsmoking patients. In addition, we demonstrated that these signaling pathways strongly influence the proliferation and differentiation state of in vitro-generated normal human airway epithelial basal cells. Finally, we exposed mice to cigarette smoke for 16 weeks, and demonstrated that anti-TNF-alpha (etanercept), anti-IL-1 beta (anakinra), and/or anti-IL-6R (tocilizumab) therapies significantly reduced epithelial hyperplasia and the development of squamous metaplasia. These data highlight the importance of soluble inflammatory mediators in the pathogenesis of tracheobronchial squamous metaplasia. Therefore, the administration of proinflammatory cytokine antagonists may have clinical applications in the management of patients with COPD.