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首页> 外文期刊>The Internet Journal of Asthma, Allergy and Immunology >In Vitro Exposure To Cigarette Smoke Activates Eosinophils: Implications For Lung Inflammation
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In Vitro Exposure To Cigarette Smoke Activates Eosinophils: Implications For Lung Inflammation

机译：体外暴露于香烟烟雾会激活嗜酸性粒细胞：对肺炎症的影响

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Effects of cigarette smoke (CS) on eosinophils (EOS), important cells involved in the pathogenesis of chronic lung diseases such as asthma, were studied in vitro. EOS were isolated from healthy and mildly atopic donors and exposed to soluble components of cigarette smoke (CSE). Viability and apoptosis were assessed by flow cytometry after staining with propidium iodide and Annexin-V. Activation was determined by release of newly-synthesized (IL-8, IL-6) mediators and by phosphorylation of MAPKs. CSE effects on ultrastructural morphology and production of neutrophil chemotactic factors in CSE-activated EOS were also evaluated. CSE concentrations from 0-2.5% were non-toxic for up to 18-24 hours of exposure. However, CSE at 2.5% activated EOS as evidenced by ultrastructural degranulation: release of IL-8 and IL-6, and increased expression of the MAPK, c-Jun. Supernatants from CSE-activated EOS were found to be significantly chemotactic for neutrophils. These results suggest that CS may aggravate lung inflammation by activating EOS which, in turn, release inflammatory mediators promoting inflammatory cell recruitment and lung remodeling. Introduction Eosinophils (EOS) are terminally differentiated granular leukocytes that are produced in the bone marrow and migrate to inflamed tissues in response to chemotactic signals. Their recruitment, growth and survival are supported by cytokines and chemokines such as granulocyte-macrophage colony stimulating factor (GM-CSF), and interleukins (IL)- 3 and -5 [1,2,3,4]. Eosinophilia occurs in response to parasitic infection and exposure to allergens. Eosinophils are particularly evident in chronic lung inflammation where their products appear to play roles both in bronchial hyper-responsiveness and in tissue remodeling, leading to compromised lung function [5,6]. Increased numbers of eosinophils in the bronchial mucosa have been correlated with a number of conditions such as: bronchial wall thickening, epithelial cell hypertrophy, and myofibroblast hyperplasia [7]; Goblet cell hyperplasia and increased mucus production [7]; and tissue remodeling [8]; and fibrosis [9]. Neutralization of IL-5, the main eosinophil growth factor, has been shown to block airway hyper-reactivity [10].Many of the eosinophil mediators involved in the pathogenesis of airway inflammation are preformed and stored in granules that are released upon eosinophil activation. These include: major basic protein (MBP) whose levels are correlated with bronchial epithelial damage [11]; eosinophil cationic protein (ECP) which has been shown to be elevated in chronic asthma and associated with airflow obstruction [12]; eosinophil-derived neurotoxin (ECN) which stimulates fibroblast proliferation [13]; and eosinophil peroxidase (EPO) which catalyzes the peroxidation of halides and forms toxic nitrogen reactive species that contribute to asthmatic inflammation [14]. EPO, which is used as a biomarker of eosinophil degranulation (i.e., activation) [15], inactivates leukotrienes that cause bronchoconstriction [16]. MBP, the main granule constituent also induces degranulation of tissue mast cells, which contribute to airway hyper-responsiveness and inflammation [17]. Additionally, eosinophil cytoplasmic lipid bodies contain cyclooxygenases (COX), lipoxygenases, and phospholipase A2, all of which contribute to inflammation through their role in synthesis of proinflammatory eicosanoids [18]. Upon activation, eosinophils also synthesize and release a variety of proinflammatory cytokines including: the interleukins IL-1α, IL-6, IL-8; tumor necrosis factor- alpha (TNF-α); transforming growth factors (TGF)-α and β and eotaxin [19,20]. TNF-α, which is also produced by several other inflammatory cell types, causes recruitment of eosinophils and neutrophils to inflamed tissues, induces eosinophil synthesis and release of matrix metalloproteinases (MMPs) involved in lung tissue remodeling, and synergizes with GM-CSF to promoting eosinophil survival
机译：体外研究了香烟烟雾（CS）对嗜酸性粒细胞（EOS）的影响，嗜酸性粒细胞是参与慢性肺部疾病如哮喘发病机理的重要细胞。从健康和轻度过敏性供体中分离出EOS，并将其暴露于香烟烟雾（CSE）的可溶性成分中。用碘化丙锭和膜联蛋白-V染色后，通过流式细胞术评估生存力和凋亡。激活是通过释放新合成的（IL-8，IL-6）介体并通过MAPK磷酸化来确定的。还评估了CSE对CSE活化EOS中超微结构形态和中性粒细胞趋化因子产生的影响。从0-2.5％的CSE浓度在暴露至18-24小时内无毒。然而，超微结构脱粒证明CSE的浓度为2.5％时会激活EOS：释放IL-8和IL-6，并增加MAPK c-Jun的表达。发现来自CSE活化EOS的上清液对嗜中性粒细胞具有明显的趋化作用。这些结果表明，CS可能会通过激活EOS加剧肺部炎症，而EOS继而释放出促进炎症细胞募集和肺重构的炎症介质。简介嗜酸性粒细胞（EOS）是终末分化的粒状白细胞，在骨髓中产生并响应趋化信号迁移到发炎的组织。它们的募集，生长和存活得到细胞因子和趋化因子的支持，例如粒细胞-巨噬细胞集落刺激因子（GM-CSF），白介素（IL）-3和-5 [1,2,3,4]。嗜酸性粒细胞增多是对寄生虫感染和过敏原的反应。嗜酸性粒细胞在慢性肺部炎症中尤为明显，其产物在支气管高反应性和组织重塑中均起着作用，导致肺功能受损[5,6]。支气管粘膜中嗜酸性粒细胞数量的增加与多种疾病相关，例如：支气管壁增厚，上皮细胞肥大和成肌纤维细胞增生[7];杯状细胞增生和粘液产生增加[7];和组织重塑[8];和纤维化[9]。 IL-5（主要的嗜酸性粒细胞生长因子）的中和已被证明可阻止气道高反应性[10]。许多参与气道炎症发病机制的嗜酸性粒细胞介体均预先制成并储存在颗粒中，并在嗜酸性粒细胞活化后释放。这些包括：主要碱性蛋白（MBP），其水平与支气管上皮损伤有关[11];嗜酸性粒细胞阳离子蛋白（ECP）已被证明在慢性哮喘中升高，并与气流阻塞有关[12];嗜酸性粒细胞衍生的神经毒素（ECN），刺激成纤维细胞增殖[13];嗜酸性粒细胞过氧化物酶（EPO）催化卤化物的过氧化反应并形成有毒的氮反应性物种，从而导致哮喘发炎[14]。 EPO用作嗜酸性粒细胞脱粒（即活化）的生物标志物[15]，可以使引起支气管收缩的白三烯失活[16]。 MBP是主要的颗粒成分，它还诱导组织肥大细胞脱粒，这有助于气道高反应性和炎症[17]。此外，嗜酸性粒细胞胞质脂质体还包含环氧合酶（COX），脂氧合酶和磷脂酶A2，它们均通过其在促炎性类花生酸合成中的作用而促成炎症[18]。活化后，嗜酸性粒细胞还合成并释放多种促炎细胞因子，包括：白介素IL-1α，IL-6，IL-8;白介素IL-1α，IL-6，IL-8;白介素IL-1α，IL-6，IL-8。肿瘤坏死因子-α（TNF-α）;转化生长因子（TGF）-α，β和嗜酸性粒细胞趋化因子[19,20]。 TNF-α也由其他几种炎性细胞类型产生，导致嗜酸性粒细胞和嗜中性粒细胞募集到发炎的组织，诱导嗜酸性粒细胞合成和基质金属蛋白酶（MMP）的释放，参与肺组织重塑，并与GM-CSF协同促进嗜酸性粒细胞存活

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