This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matheson, J. M. Articles by Luster, M. I. Search for Related Content PubMed PubMed Citation Articles by Matheson, J. M. Articles by Luster, M. I.

Role of Tumor Necrosis Factor in Toluene Diisocyanate Asthma

Toxicology and Molecular Biology Branch, Health Effects Laboratory Division, National Institute for Occupational Safety and Health, Morgantown, West Virginia; Center for Environmental and Occupational Health and Toxicology, University of Pittsburgh, Pittsburgh, Pennsylvania; and Pathology and Toxicology, 3M Pharmaceuticals, St. Paul, Minnesota

Address correspondence to: 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. E-mail: yzm9{at}cdc.gov

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)- being critical to this process. To explore this hypothesis, wild-type mice, athymic mice, TNF- receptor knockout (TNFR), and anti–TNF- antibody–treated mice were sensitized by subcutaneous injection (20 µl on Day 1; 5 µl, 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- null mice and athymic mice. TNF- 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- 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- 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- has multiple and central roles in TDI-induced asthma, influencing both nonspecific inflammatory processes and specific immune events.

Abbreviations: airway hyperresponsiveness, AHR • bronchoalveolar lavage fluid, BALF • complementary DNA, cDNA • TNF- double receptor knockout, DKO • enzyme-linked immunosorbent assay, ELISA • fluorescence-activated cell sorter, FACS • fluorescein-conjugated isothiocyanate, FITC • de-3-phosphate-dehydrogenase, G3PDH • interferon, IFN • interleukin, IL • lymphotactin, Ltn • lymphotoxin ß, Ltß • enhanced pause, Penh • parts per billion, ppb • reverse transcription-polymerase chain reaction, RT-PCR • glyceraldehyde ribonuclease protection assay, RPA • toluene diisocyanate, TDI • tumor necrosis factor, TNF • TNF- receptor knockout, TNFR • TNF- receptor 1 (p55) knockout, TNFR1 • TNF- receptor 1 (p75) knockout, TNFR2

This article has been cited by other articles:

				K. J. Szretter, S. Gangappa, X. Lu, C. Smith, W.-J. Shieh, S. R. Zaki, S. Sambhara, T. M. Tumpey, and J. M. Katz Role of Host Cytokine Responses in the Pathogenesis of Avian H5N1 Influenza Viruses in Mice J. Virol., March 15, 2007; 81(6): 2736 - 2744. [Abstract] [Full Text] [PDF]

				J. M. Matheson, V. J. Johnson, and M. I. Luster Immune Mediators in a Murine Model for Occupational Asthma: Studies with Toluene Diisocyanate Toxicol. Sci., March 1, 2005; 84(1): 99 - 109. [Abstract] [Full Text] [PDF]

				J. A. J. Vanoirbeek, M. Tarkowski, J. L. Ceuppens, E. K. Verbeken, B. Nemery, and P. H. M. Hoet Respiratory Response to Toluene Diisocyanate Depends on Prior Frequency and Concentration of Dermal Sensitization in Mice Toxicol. Sci., August 1, 2004; 80(2): 310 - 321. [Abstract] [Full Text] [PDF]

				J. Elias The Relationship Between Asthma and COPD: Lessons From Transgenic Mice Chest, August 1, 2004; 126(2_suppl_1): 111S - 116S. [Abstract] [Full Text] [PDF]

				H. Wan, K. H. Kaestner, S.-L. Ang, M. Ikegami, F. D. Finkelman, M. T. Stahlman, P. C. Fulkerson, M. E. Rothenberg, and J. A. Whitsett Foxa2 regulates alveolarization and goblet cell hyperplasia Development, February 15, 2004; 131(4): 953 - 964. [Abstract] [Full Text] [PDF]

				J. A. J. Vanoirbeek, C. Mandervelt, A. R. Cunningham, P. H. M. Hoet, H. Xu, H. M. Vanhooren, and B. Nemery Validity of Methods to Predict the Respiratory Sensitizing Potential of Chemicals: A Study with a Piperidinyl Chlorotriazine Derivative That Caused an Outbreak of Occupational Asthma Toxicol. Sci., December 1, 2003; 76(2): 338 - 346. [Abstract] [Full Text] [PDF]

				J. Sastre, O. Vandenplas, and H-S. Park Pathogenesis of occupational asthma Eur. Respir. J., August 1, 2003; 22(2): 364 - 373. [Abstract] [Full Text] [PDF]

				C.E. Mapp The role of genetic factors in occupational asthma Eur. Respir. J., July 1, 2003; 22(1): 173 - 178. [Abstract] [Full Text] [PDF]

				C. A. Redlich, A. V. Wisnewski, and T. Gordon Mouse Models of Diisocyanate Asthma Am. J. Respir. Cell Mol. Biol., October 1, 2002; 27(4): 385 - 390. [Full Text] [PDF]