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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
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
Contact
Dr. Joanna Matheson, Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, 1095 Willowdale Road, Ms 3014, Morgantown WV 26505
CODEN
AJRBEL
CAS No.
584-84-9
Publication Date
20021001
Document Type
Journal Article
Email Address
yzm9@cdc.gov
Fiscal Year
2003
NTIS Accession No.
NTIS Price
Issue of Publication
4
ISSN
1044-1549
NIOSH Division
HELD
Priority Area
Disease and Injury; Asthma and Chronic Obstructive Pulmonary Disease
Source Name
American Journal Respiratory Cell and Molecular Biology
State
WV; PA; MI
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