Arts Josje H E, Bloksma Nanne, Leusink-Muis Thea, Kuper C Frieke
Toxicology Division, TNO Nutrition and Food Research, Zeist, The Netherlands.
Toxicol Appl Pharmacol. 2003 Feb 15;187(1):38-49. doi: 10.1016/s0041-008x(02)00023-6.
Occupational exposure to low-molecular-weight (LMW) allergens such as acid anhydrides can result in occupational asthma, an allergic disease characterized by episodic airway obstruction, airways inflammation, and non specific airways hyperresponsiveness. Since LMW irritants can provoke rather similar effects and since most, if not all, LMW allergens have irritant properties, this study addressed the distinction between allergenic and irritant effects of the respiratory allergen trimellitic anhydride (TMA). BN rats were sensitized by dermal application of TMA or vehicle alone and 3 weeks later were challenged by inhalation of a slightly irritating concentration of TMA or the vehicle. Lung function was measured before, during, and shortly after challenge. One day after challenge, in vivo and in vitro nonspecific airways hyperresponsiveness to methacholine was measured, and bronchoalveolar lavage was performed to measure total protein, lactate dehydrogenase, N-acetyl-glucosaminidase, and total and differential leukocyte numbers in the fluid. In addition, IgE measurements and histopathological examinations of the respiratory tract were carried out. TMA challenge of sensitized, but not sham-sensitized, BN rats reduced breathing frequency during challenge, elevated total and TMA-specific serum IgE levels, and caused a typical allergic asthma-associated airway pathology, as observed earlier. Vehicle challenge did not cause these effects, irrespective of sensitization. Hyperresponsiveness to methacholine was only seen in TMA-sensitized and -challenged rats. These rats also showed increased levels of the biochemical parameters and increased numbers of eosinophils and neutrophils in the lung lavage fluid; TMA challenge of sham-sensitized rats caused similar but markedly less pronounced effects. During TMA challenge of sham-sensitized rats, a breathing pattern typical of irritation was noticed but a clearly distinct pattern was seen upon TMA challenge of sensitized rats. In conclusion, TMA challenge of sensitized rats caused sensitization-dependent asthma-like early changes in breathing pattern that clearly could be distinguished from irritant-induced changes and non-specific airways hyperresponsiveness 24 h after challenge. Sensitization-dependent functional changes were accompanied by inflammatory changes characteristic of asthma and biochemical evidence of airway damage.
职业性接触低分子量（LMW）变应原，如酸酐，可导致职业性哮喘，这是一种以发作性气道阻塞、气道炎症和非特异性气道高反应性为特征的过敏性疾病。由于低分子量刺激物可引发相当相似的效应，而且大多数（即便不是全部）低分子量变应原都具有刺激特性，因此本研究探讨了呼吸道变应原偏苯三酸酐（TMA）的变应原性效应与刺激性效应之间的区别。通过经皮应用TMA或单独使用赋形剂使BN大鼠致敏，3周后通过吸入轻微刺激性浓度的TMA或赋形剂对其进行激发。在激发前、激发期间和激发后不久测量肺功能。激发后一天，测量体内和体外对乙酰甲胆碱的非特异性气道高反应性，并进行支气管肺泡灌洗以测量灌洗液中的总蛋白、乳酸脱氢酶、N - 乙酰 - 氨基葡萄糖苷酶以及总白细胞数和分类白细胞数。此外，还进行了IgE测量以及呼吸道的组织病理学检查。如先前观察到的那样，对致敏的（而非假致敏的）BN大鼠进行TMA激发会降低激发期间的呼吸频率，提高血清总IgE水平和TMA特异性IgE水平，并导致典型的与过敏性哮喘相关的气道病理改变。无论是否致敏，赋形剂激发均未引起这些效应。仅在TMA致敏并激发的大鼠中观察到对乙酰甲胆碱的高反应性。这些大鼠在肺灌洗液中的生化参数水平也升高，嗜酸性粒细胞和中性粒细胞数量增加；对假致敏大鼠进行TMA激发会引起类似但明显较轻的效应。在对假致敏大鼠进行TMA激发期间，注意到一种典型的刺激呼吸模式，但在对致敏大鼠进行TMA激发时则观察到明显不同的模式。总之，对致敏大鼠进行TMA激发会导致与致敏相关的哮喘样早期呼吸模式变化，在激发24小时后这种变化明显可与刺激诱导的变化和非特异性气道高反应性区分开来。与致敏相关的功能变化伴有哮喘特征性的炎症变化以及气道损伤的生化证据。
