Harkema Jack R, Wagner James G, Kaminski Norbert E, Morishita Masako, Keeler Gerald J, McDonald Jacob D, Barrett Edward G
Department of Pathobiology and Diagnostic Investigation, Michigan State University, East Lansing, Michigan 48864, USA.
Res Rep Health Eff Inst. 2009 Nov(145):5-55.
Increased concentrations of airborne fine particulate matter (PM2.5; particulate matter with an aerodynamic diameter < or = 2.5 microm) are associated with increases in emergency room visits and hospitalizations of asthmatic patients. Emissions from local stationary combustion sources (e.g., coal-burning power plants) or mobile motor vehicles (e.g., diesel-powered trucks) have been identified as potential contributors to the development or exacerbation of allergic airway disease. In the present study, a rodent model of allergic airway disease was used to study the effects of concentrated ambient particles (CAPs) or diesel engine exhaust (DEE) on the development of allergic airway disease in rats sensitized to the allergen ovalbumin (OVA). The overall objective of our project was to understand the effects of PM2.5 on the development of OVA-induced allergic airway disease. Our specific aims were to test the following hypotheses: (1) exposure to CAPs during OVA challenge enhances epithelial remodeling of the airway and inflammation in rats previously sensitized to the allergen; and (2) exposure to DEE during OVA sensitization, or during OVA challenge, exacerbates epithelial remodeling of the airway and inflammation in rats. In the DEE studies, Brown Norway (BN) rats were sensitized with three daily intranasal (IN) instillations of 0.5% OVA, and then two weeks later were challenged with IN OVA or saline for 3 consecutive days. Rats were exposed to DEE diluted to mass concentrations of 30 or 300 microg/m3 diesel exhaust particles (DEPs) or to filtered air during either the sensitization or challenge periods. For the CAPs studies, the same OVA sensitization and challenge rat model was used but exposures to Detroit, Michigan, CAPs were limited to the OVA challenge period. Two separate 3-day CAPs exposures were conducted (week 1, high mean mass concentration = 595 microg/m3; week 2, low mean mass concentration = 356 microg/m3) during OVA challenge. In both the DEE and CAPs studies, rats were killed 24 hours after the last OVA challenge, bronchoalveolar lavage fluid (BALF) was collected and analyzed for cellularity and secreted mediators, and lungs and nose were processed for histopathologic examination and morphometric analysis of intraepithelial mucosubstances (IM). The results of our animal inhalation studies in the southwest (SW) Detroit community, an area with elevated ambient PM2.5 concentrations, suggested that, during allergen challenge, exposure to CAPs that were predominantly associated with emissions from combustion sources markedly enhanced the OVA-induced allergic airway disease, which was characterized by an increased infiltration in the lungs of eosinophilic and lymphocytic inflammation, increased IM in conducting airways, and increased concentrations in BALF of mucin-specific proteins and inflammatory cytokines. These findings suggest that urban airborne PM2.5 derived from stationary combustion sources (e.g., refineries, coal-burning power plants, waste-treatment plants) may enhance the development of human allergic airway diseases like childhood asthma. Previous animal inhalation studies in this community have also suggested that these fine, ambient combustion-derived particles may also exacerbate preexisting allergic airway disease. In contrast to our CAPs studies in Detroit, the controlled DEE exposures of allergen-sensitized BN rats, during either allergen sensitization or challenge periods, caused only a few mild modifications in the character of the allergen-induced disease. This finding contrasts with other reported studies that indicate that DEPs at relatively higher exposure doses do enhance allergic airway disease in some rodent models. The reasons for these disparities between studies likely reflect differences in exposure dose, animal models, the timing of exposures to the allergens and DEP exposures, the methods of allergen sensitization and challenge, or physicochemical differences among DEEs.
空气中细颗粒物(PM2.5;空气动力学直径小于或等于2.5微米的颗粒物)浓度增加与哮喘患者急诊就诊和住院人数增加有关。当地固定燃烧源(如燃煤发电厂)或移动机动车辆(如柴油卡车)的排放已被确定为过敏性气道疾病发生或加重的潜在因素。在本研究中,使用过敏性气道疾病的啮齿动物模型来研究浓缩环境颗粒物(CAPs)或柴油机尾气(DEE)对致敏于卵清蛋白(OVA)的大鼠过敏性气道疾病发展的影响。我们项目的总体目标是了解PM2.5对OVA诱导的过敏性气道疾病发展的影响。我们的具体目标是检验以下假设:(1)在OVA激发期间暴露于CAPs会增强先前致敏于该过敏原的大鼠气道上皮重塑和炎症;(2)在OVA致敏期间或OVA激发期间暴露于DEE会加剧大鼠气道上皮重塑和炎症。在DEE研究中,用0.5%OVA每日经鼻(IN)滴注3天使棕色挪威(BN)大鼠致敏,然后两周后用IN OVA或生理盐水连续激发3天。在致敏或激发期间,将大鼠暴露于稀释至质量浓度为30或300微克/立方米柴油机尾气颗粒(DEPs)的DEE中或过滤空气中。对于CAPs研究,使用相同的OVA致敏和激发大鼠模型,但将密歇根州底特律的CAPs暴露限制在OVA激发期。在OVA激发期间进行了两次单独的为期3天的CAPs暴露(第1周,高平均质量浓度=595微克/立方米;第2周,低平均质量浓度=356微克/立方米)。在DEE和CAPs研究中,在最后一次OVA激发后24小时处死大鼠,收集支气管肺泡灌洗液(BALF)并分析细胞成分和分泌介质,对肺和鼻进行组织病理学检查和上皮内黏液物质(IM)的形态计量分析。我们在底特律西南部(SW)社区进行的动物吸入研究结果表明,该地区环境PM2.5浓度升高,在过敏原激发期间,暴露于主要与燃烧源排放相关的CAPs会显著增强OVA诱导的过敏性气道疾病,其特征是肺中嗜酸性粒细胞和淋巴细胞炎症浸润增加、传导气道中IM增加以及BALF中黏蛋白特异性蛋白和炎性细胞因子浓度增加。这些发现表明,源自固定燃烧源(如炼油厂、燃煤发电厂、废物处理厂)的城市空气中PM2.5可能会促进人类过敏性气道疾病如儿童哮喘的发展。此前在该社区进行的动物吸入研究也表明,这些细小的、源自环境燃烧的颗粒也可能会加重已有的过敏性气道疾病。与我们在底特律进行的CAPs研究不同,在过敏原致敏或激发期间对致敏于过敏原的BN大鼠进行的受控DEE暴露,仅在过敏原诱导疾病的特征上引起了一些轻微改变。这一发现与其他报道的研究形成对比,那些研究表明在一些啮齿动物模型中,相对较高暴露剂量的DEPs确实会增强过敏性气道疾病。研究之间这些差异的原因可能反映了暴露剂量、动物模型、暴露于过敏原和DEP暴露的时间、过敏原致敏和激发方法或DEE之间的物理化学差异。
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