Glutathione-conjugated toluene diisocyanate causes airway inflammation in sensitised mice (original) (raw)

2004, Archives of Toxicology

Asthma is the most common chronic respiratory disease in the world. An estimated 300 million people of all ages and all ethnic backgrounds suffer from asthma and the morbidity and mortality associated with it are increasing in industrialized nations (Global burden of Asthma, 2004, www.ginasthma.com). The major clinical symptoms of asthma include coughing, wheezing, shortness of breath, and chest tightness, alone or in combination and these symptoms may vary from mild to life threatening. The symptoms are due to reversible airflow obstruction, persistent airway hyperresponsiveness, airway inflammation, mucus hypersecretion, and airway remodeling (1). In general, asthma can be divided in two groups. The majority of asthmatics (approximately 70%) has atopic asthma and display increased IgE levels in their serum, the remainder has nonatopic asthma and exhibit normal IgE levels. A recent study, however, provided evidence of local IgE synthesis in the bronchial mucosa of both atopic and nonatopic asthmatics (2). Furthermore, increased numbers of Fcε-receptor-bearing cells were identified in bronchial biopsies from atopic and nonatopic asthmatics (3) indicating that the underlying mechanisms of both types of asthma might be very similar. The development of asthma requires sensitization to environmental allergens, like house dust mite and animal dander (4-6). Allergens are taken up and processed by antigen-presenting cells, like the dendritic cells that are abundantly present in the submucosa of the airways (7). These cells then migrate to the local lymph node where the processed allergen is presented to allergenspecific T cells, inducing T cell differentiation and memory (8). These T cells then secrete cytokines, like interleukin 4 (IL-4) and IL-13, that induce proliferation of, and IgE production by allergenrecognizing B cells (9). Allergen-specific IgE will then bind to FcεRI on the surface of mast cells lining the airways (10). Cross-linking of mast cell-bound IgE upon re-exposure to the allergen will lead to the release of mediators, like histamine and leukotrienes, by these cells (10). In general, these mast cell-derived mediators induce airway constriction, increase vascular permeability, enhance airway responsiveness, induce mucus secretion, and promote the recruitment of inflammatory cells, like eosinophils, T cells, and macrophages, into the airways (11). In addition to resident cells, like epithelial cells, endothelial cells, and smooth muscle cells, these inflammatory cells can produce a vast array of inflammatory mediators, like chemokines, cytokines and leukotrienes (12), promoting the chronic characteristic of the airway inflammation after repeated allergen exposure. As a result of this chronic inflammation, airway tissue is continuously being injured and healed, leading to structural changes of the airways that may account for the decline in airway function seen in patients over the years (13).