Role of Tumor Necrosis Factor in Toluene Diisocyanate Asthma

Details

• Personal Author:
  Karol MH ; Lange RW ; Lemus R ; Luster MI ; Matheson JM ; Karol MH ; Lange RW ; Lemus R ; Luster MI ; Matheson JM
• Description:
  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. [Description provided by NIOSH]
• Subjects:
  Animals Chelating Agents Hypersensitivity Immune System Irritants Isocyanates Laboratories Lung Methacholine Compounds Neoplasms Occupational Health Respiratory System Respiratory Tract Diseases Safety

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• Keywords:
  Airway-obstruction Airway-resistance Animal-studies Cell-damage Chelating-agents Immune-reaction Laboratory-animals Lung-irritants Methacholines Pulmonary-system-disorders Respiratory-system-disorders Sensitization Tumors

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• ISSN:
  1044-1549
• Document Type:
  Text
• Genre:
  Journal Article ; Journal Article
• Place as Subject:
  Michigan ; OSHA Region 3 ; OSHA Region 5 ; Pennsylvania ; West Virginia
• CIO:
  National Institute for Occupational Safety and Health (NIOSH) ; National Institute for Occupational Safety and Health (NIOSH)
• Division:
  HELD - Health Effects Laboratory Division ; HELD - Health Effects Laboratory Division
• Topic:
  Workplace Safety & Health ; Workplace Safety & Health
• Location:
  North America ; North America
• Pages in Document:
  396-405
• Volume:
  27
• Issue:
  4
• NIOSHTIC Number:
  nn:20022845
• Citation:
  Am J Respir Cell Mol Biol 2002 Oct; 27(4):396-405
• Contact Point Address:
  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
• Email:
  yzm9@cdc.gov
• CAS Registry Number:
  Toluene 2,4-diisocyanate (CAS RN 584-84-9) ; Toluene 2,4-diisocyanate (CAS RN 584-84-9)
• Federal Fiscal Year:
  2003
• NORA Priority Area:
  Disease and Injury: Asthma and Chronic Obstructive Pulmonary Disease ; Disease and Injury: Asthma and Chronic Obstructive Pulmonary Disease
• Peer Reviewed:
  True
• Source Full Name:
  American Journal of Respiratory Cell and Molecular Biology
• Collection(s):
  National Institute for Occupational Safety and Health
• Main Document Checksum:
  urn:sha-512:552e78345a2b39af33969599c79b3cd59cf79e23845c89bbe79dbdcfc3d6a8b69c70b82a7df74f797193dd8230ddd276163760baa9a64bf9e4a50083c5026397
• Download URL:
  https://stacks.cdc.gov/view/cdc/199477/cdc_199477_DS1.pdf
• File Type:
  [PDF - 331.66 KB ]