Matheson Joanna M, Lemus Ranulfo, Lange Robert W, Karol Meryl H, Luster Michael I
Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia 26505, USA.
Am J Respir Cell Mol Biol. 2002 Oct;27(4):396-405. doi: 10.1165/rcmb.4614.
Nearly 9 million workers are exposed to chemical agents associated with occupational asthma, with isocyanates representing the chemical class most responsible. Isocyanate-induced asthma has been difficult to diagnose and control, in part because the biologic mechanisms responsible for the disease and the determinants of exposure have not been well defined. Isocyanate-induced asthma is characterized by airway inflammation, and we hypothesized that inflammation is a prerequisite of isocyanate-induced asthma, with tumor necrosis factor (TNF)-alpha being critical to this process. To explore this hypothesis, wild-type mice, athymic mice, TNF-alpha receptor knockout (TNFR), and anti-TNF-alpha antibody-treated mice were sensitized by subcutaneous injection (20 micro l on Day 1; 5 micro l, Days 4 and 11), and challenged 7 d later by inhalation (100 ppb; Days 20, 22, and 24) with toluene diisocyanate (TDI). Airway inflammation, goblet cell metaplasia, epithelial cell damage, and nonspecific airway reactivity to methacholine challenge, measured 24 h following the last challenge, were reduced to baseline levels in TNF-alpha null mice and athymic mice. TNF-alpha deficiency also markedly abrogated TDI-induced Th2 cytokines in airway tissues, indicating a role in the development of Th2 responses. Despite abrogation of all indicators of asthma pathology, TNF-alpha neutralization had no effect on serum IgE levels or IgG-specific TDI antibodies, suggesting the lack of importance of a humoral response in the manifestation of TDI-induced asthma. Instillation studies with fluorescein-conjugated isothiocyanate and TDI suggested that TNF-alpha deficiency also resulted in a significant reduction in the migration of airway dendritic cells to the draining lymph nodes. Taken together, these results suggest that, unlike protein antigens, TNF-alpha has multiple and central roles in TDI-induced asthma, influencing both nonspecific inflammatory processes and specific immune events.
近900万工人接触与职业性哮喘相关的化学制剂，其中异氰酸酯是最主要的化学类别。异氰酸酯诱发的哮喘难以诊断和控制，部分原因是导致该疾病的生物学机制以及接触的决定因素尚未明确界定。异氰酸酯诱发的哮喘以气道炎症为特征，我们推测炎症是异氰酸酯诱发哮喘的先决条件，肿瘤坏死因子（TNF）-α在此过程中起关键作用。为了探究这一假设，通过皮下注射（第1天20微升；第4天和第11天各5微升）使野生型小鼠、无胸腺小鼠、TNF-α受体敲除（TNFR）小鼠以及抗TNF-α抗体处理的小鼠致敏，并在7天后通过吸入（100 ppb；第20天、22天和24天）甲苯二异氰酸酯（TDI）进行激发。在最后一次激发后24小时测量气道炎症、杯状细胞化生、上皮细胞损伤以及对乙酰甲胆碱激发的非特异性气道反应性，结果显示在TNF-α基因敲除小鼠和无胸腺小鼠中这些指标均降至基线水平。TNF-α缺乏还显著消除了气道组织中TDI诱导的Th2细胞因子，表明其在Th2反应发展中起作用。尽管消除了哮喘病理的所有指标，但TNF-α中和对血清IgE水平或IgG特异性TDI抗体没有影响，这表明体液反应在TDI诱发哮喘的表现中并不重要。用荧光素偶联异硫氰酸酯和TDI进行的滴注研究表明，TNF-α缺乏还导致气道树突状细胞向引流淋巴结迁移的显著减少。综上所述，这些结果表明，与蛋白质抗原不同，TNF-α在TDI诱发的哮喘中具有多种核心作用，影响非特异性炎症过程和特异性免疫事件。
