Isocyanate-induced asthma, the most commonly reported cause of occupational asthma, has been difficult to diagnose and control, in part, because the biological mechanisms responsible for the disease and the determinants of exposure have been difficult to define. Appropriate animals models of isocyanate asthma will be instrumental to further our understanding of this disease. Previous studies have demonstrated that dermal exposure to isocyanates in mice results in systemic sensitization that leads to eosinophilic airways inflammation upon subsequent airway challenge. We hypothesized that inhalation of vapor phase toluene diisocyante (TDI) will lead to immunologic sensitization in mice and that subsequent challenge will induce pathology and immune system alterations indicative of asthma found in humans. To determine the impact of exposure dose as well as the involvement of immune (allergic) or nonimmune mechanisms, a murine model of TDI asthma was established and characterized following either low-level subchronic or high-dose acute inhalation TDI exposure. C57BL/6 J mice were exposed to TDI by inhalation either subchronically for 6 weeks (20 ppb, 4 h/day, 5 days/week) or by a 2-h acute exposure at 500 ppb. Both groups were challenged 14 days later via inhalation with 20 ppb TDI for 1 h. Mice that underwent the subchronic exposure regimen demonstrated a marked allergic response evidenced by increases in airway inflammation, eosinophilia, goblet cell metaplasia, epithelial cell alterations, airway hyperreponsiveness (AHR), T(H)1/T(H)2 cytokine expression in the lung, elevated levels of serum IgE, and TDI-specific IgG antibodies, as well as the ability to transfer these pathologies to naive mice with lymphocytes or sera from TDI exposed mice. In contrast, mice that received acute TDI exposure demonstrated increased AHR, specific IgG antibodies, and pathology in the lung consistent with asthma, but without the presence of elevated serum IgE, lung eosionophilia, or increased expression of T(H) cytokines. These results describe mouse models for TDI asthma consistent with that found in workers with occupational asthma and indicate that the pulmonary pathology associated with TDI can vary depending upon the exposure paradigm.

译文

异氰酸酯引起的哮喘是职业性哮喘的最常见原因,很难诊断和控制,部分原因是难以确定导致该疾病的生物学机制和暴露的决定因素。适当的异氰酸酯哮喘动物模型将有助于我们进一步了解这种疾病。先前的研究表明,小鼠的皮肤暴露于异氰酸酯会导致全身性致敏,从而在随后的气道攻击后导致嗜酸性气道炎症。我们假设吸入气相甲苯二异氰酸酯 (TDI) 将导致小鼠的免疫敏化,随后的挑战将诱导病理和免疫系统改变,表明在人类中发现哮喘。为了确定暴露剂量的影响以及免疫 (过敏) 或非免疫机制的参与,建立了TDI哮喘的小鼠模型,并在低水平亚慢性或高剂量急性吸入TDI暴露后进行了表征。C57BL/6 j小鼠通过亚时吸入6周 (20 ppb,4小时/天,5天/周) 或通过2小时急性暴露于500 ppb暴露于TDI。两组在14天后通过吸入20 ppb TDI攻击1小时。接受亚慢性暴露方案的小鼠表现出明显的过敏反应,表现为气道炎症,嗜酸性粒细胞增多,杯状细胞化生,上皮细胞改变,气道高反应性 (AHR),T(H)1/T(H)2细胞因子表达增加。肺,血清IgE水平升高,和TDI特异性IgG抗体,以及将这些病理转移到具有TDI暴露小鼠的淋巴细胞或血清的幼稚小鼠的能力。相反,接受急性TDI暴露的小鼠表现出与哮喘一致的AHR,特异性IgG抗体和肺部病理升高,但没有血清IgE升高,肺嗜酸性粒细胞或T(H) 细胞因子表达增加。这些结果描述了TDI哮喘的小鼠模型,与职业性哮喘工人的模型一致,并表明与TDI相关的肺部病理可以根据暴露范例而变化。

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