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Role of tumor necrosis factor in toluene diisocyanate asthma |
| Authors |
Matheson-JM; Lemus-R; Lange-RW; Karol-MH; Luster MI |
| Source |
Am J Respir Cell Mol Biol 2002 Oct; 27(4):396-405 |
| Link |
http://ajrcmb.atsjournals.org/cgi/content/full/27/4/396 |
| NIOSHTIC No. |
20022845 |
| Abstract | 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. | | Keywords | Chelating-agents; Lung-irritants; Lung; Isocyanates; Irritants; Airway-obstruction; Airway-resistance; Tumors; Sensitization; Animal-studies; Animals; Cell-damage; Methacholines; Immune-reaction; Laboratory-animals; Pulmonary-system-disorders; Respiratory-system-disorders |
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