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The role of tumor necrosis factor (TNF)alpha in toluene diisocyanate (TDI) asthma.
Matheson-JM; Lange-RW; Lemus-R; Karol-MH; Luster-MI
Toxicologist 2001 Mar; 60(1):174
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 pre-requisite of isocyanate-induced asthma with tumor necrosis factor (TNF) being critical to this process. To explore this hypothesis, TNF receptor knockout (TNFR) and anti TNF antibody treated C57BL/6J mice were sensitized by subcutaneous injection (20 ul on day 1; 5 ul, 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 TNF null mice. TNF deficiency also markedly abrogated TDI-induced Th2 cytokines in airway tissues indicating a role in the development of Th2 responses. Intratracheal instillation studies (50 ul, single dose, 0-58 mg/kg) with fluorescein-conjugated isothiocyanate (FITC) and intranasal studies (20 ul, single dose, 0-10%) with TDI suggested that TNF 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 TNF 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
Issue of Publication
The Toxicologist. Society of Toxicology 40th Annual Meeting, March 25-29, 2001, San Francisco, California
Page last reviewed: March 11, 2019
Content source: National Institute for Occupational Safety and Health Education and Information Division