title: Role of tumor necrosis factor in toluene diisocyanate asthma.
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.
mesh_terms: D000485:Allergens; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001249:Asthma / Q000139:chemically induced*; D051940:B7-2 Antigen; D016207:Cytokines / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D007073:Immunoglobulin E / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000473:pathology; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016273:Occupational Exposure; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012260:Ribonucleases / Q000378:metabolism; D013997:Time Factors; D014051:Toluene 2,4-Diisocyanate / Q000009:adverse effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: D000485:Allergens; D015703:Antigens, CD; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D016207:Cytokines; D007074:Immunoglobulin G; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D016210:Methacholine Chloride; D014051:Toluene 2,4-Diisocyanate; D015847:Interleukin-4; D007073:Immunoglobulin E; C026942:2,6-diisocyanatotoluene; D007371:Interferon-gamma; D012260:Ribonucleases