How long do the systemic and ventilatory responses to toluene diisocyanate persist in dermally sensitized mice?
BACKGROUND
Years after removal from exposure, workers with occupational asthma still show respiratory symptoms and airway hyperresponsiveness on re-exposure to the offending agent.


OBJECTIVE
We investigated the persistence of the respiratory responsiveness to toluene diisocyanate (TDI) in a mouse model.


METHODS
BALB/C mice received dermal applications of TDI on days 1 and 8, and a single intranasal instillation of TDI on day 10, 15, 20, 25, 30, 40, 50, 60, or 90. After instillation, early (1 hour) changes in ventilatory function and methacholine responsiveness (22 hours) were assessed. Cell counts and macrophage inflammatory protein 2 were measured in bronchoalveolar lavage. Total serum IgE, IgG(1), and IgG(2a) were quantified. Lymphocyte subpopulations were assessed in auricular and cervical lymph nodes, and release of IL-4 and IFN-gamma by these lymph node cells was measured.


RESULTS
Toluene diisocyanate-treated mice showed immediate ventilatory changes, increased methacholine reactivity, and an influx of neutrophils and macrophage inflammatory protein 2 in bronchoalveolar lavage as long as 50 days after initial treatment. These mice also showed a relative increase in CD19(+) cells and a decrease in CD4(+) and CD8(+) cells in auricular lymph nodes. Increased release of IL-4 and IFN-gamma in auricular lymph node cells was observed only until 20 days after sensitization. Total serum IgE, IgG(1), and IgG(2a) remained significantly elevated in TDI-sensitized mice until 90 days after dermal sensitization.


CONCLUSIONS
Ventilatory and lung inflammatory responses decrease with increasing delay between sensitization and challenge, despite persistent humoral signs of sensitization.
Vanoirbeek
Jeroen A J
JA
Laboratory of Lung Toxicology, Katholieke Universiteit Leuven, Leuven, Belgium.
De Vooght
Vanessa
V
Vanhooren
Hadewijch M
HM
Nawrot
Tim S
TS
Nemery
Benoit
B
Hoet
Peter H M
PH
D000281:Administration, Intranasal; D000818:Animals; D001835:Body Weight; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D016085:Bronchoconstrictor Agents; D054426:Chemokine CXCL2 / Q000378:metabolism; D004431:Ear, External; D007114:Immunization; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D016131:Lymphocyte Subsets / Q000473:pathology; D008297:Male; D016210:Methacholine Chloride; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000473:pathology; D012119:Respiration; D012130:Respiratory Hypersensitivity / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D012867:Skin / Q000276:immunology*; D013997:Time Factors; D014051:Toluene 2,4-Diisocyanate / Q000008:administration & dosage / Q000276:immunology*
D016085:Bronchoconstrictor Agents; D054426:Chemokine CXCL2; D007074:Immunoglobulin G; D016210:Methacholine Chloride; D014051:Toluene 2,4-Diisocyanate; D015847:Interleukin-4; D007073:Immunoglobulin E; D007371:Interferon-gamma