Matheson-JM; Lange-JW; Lemus-R; Karol-MH; Luster-MI
FASEB J 2001 Mar; 15(4):A664
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 biological 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) a being critical to this process. To explore this hypothesis, TNFa receptor knockout (TNFR) and anti- TNFa antibody treated C57BU6J mice were sensitized by subcutaneous injection (20 microliters on day 1; 5 microliters, days 4 and 11), and challenged 7 days later by inhalation (100ppb; days 20, 22 and 24) with toluene diisocyanate (TDI). Airway inflammation, goblet cell metaplasia, epithelial cell damage and non-specific airway reactivity to methacholine challenge, measured 24 hrs following the last challenge were reduced to baseline levels in TNFa null mice. TNFa deficiency also markedly abrogated TDI-induced Th2 cytokines in airway tissues indicating a role in the development of Th2 responses. Intratracheal instillation studies (50 microliters, single dose, 0-58 mg/kg) with fluorescein-conjugated isothiocyanate (FITC) and intranasal studies (20 microliters, single dose, 0-10%) with TDI suggested that TNFa 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 TNFa plays has multiple and central roles in TDI-induced asthma influencing both non-specific inflammatory processes as well as specific immune events.
Toluenes; Bronchial-asthma; Workers; Occupational-exposure; Chemical-agent-detectors; Work-environment; Isocyanates; Biological-factors; Diseases; Airway-obstruction; Cell-damage; Laboratory-animals; Animals; Animal-studies; Pulmonary-system-disorders; Respiratory-system-disorders
Abstract; Conference/Symposia Proceedings
The FASEB Journal. Experimental Biology 2001, Orlando, Florida, March 13 - April 4, 2001