Immunological determinants of ventilatory changes induced in mice by dermal sensitization and respiratory challenge with toluene diisocyanate

Abstract

The objective of the study was to characterize better the immunologic mechanisms underlying a previously developed animal model of chemical-induced asthma. BALB/c and severe combined immunodeficiency disease (SCID) mice received toluene diisocyanate (TDI) or vehicle on each ear on day 1 and/or day 7. On day 10, they were intranasally challenged with TDI or vehicle. Ventilatory function was monitored by whole body plethysmography for 40 min after challenge. Reactivity to methacholine was measured 23 h later: enhanced pause and actual resistance measurements. Pulmonary inflammation was assessed 1, 6, and 24 h after challenge by bronchoalveolar lavage (BAL). Tumor necrosis factor-alpha and macrophage inflammatory protein (MIP)-2 levels were measured in BAL. Immunological parameters included total IgE, IgG1, and IgG2a in serum, lymphocyte populations in auricular and cervical lymph nodes, and IL-4 and IFN-gamma levels in supernatants of lymph node cells, cultured with or without concanavalin A. Ventilatory changes suggestive of airway obstruction and increased methacholine reactivity were observed in all TDI-sensitized and TDI intranasally instilled mice, except in SCID mice. A neutrophil influx, accompanied by an increase in MIP-2 levels, was found in BAL of all responding groups 6 and 24 h after intranasal challenge. In BALB/c mice an increased level of CD19+ B cells was found in the auricular lymph nodes. IL-4 and IFN-gamma levels were increased in supernatants of concanavalin A-stimulated auricular lymph node cells from BALB/c mice completely treated with TDI. These results indicate that our model is dependent on the presence of lymphocytes, but it is not characterized by a preferential stimulation of Th1 or Th2 lymphocytes.

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

“…It has been shown that dermal exposure leads to respiratory tract sensitization, and several groups have reported in mice that the magnitude of respiratory responses to inhaled isocyanates (an analogous low-molecular-weight chemical OA inducer) depends on prior frequency and concentration of dermal sensitization [30][31][32]. Relatedly, we found no statistical differences in IL-13 and IFN-g cytokine levels measured in the BALFs regardless of AP-mediated asthma induction.…”

“…However, this response was transient and did appear to compromise neither the health of the treated mice nor the therapeutic potential of hASCs. We and others have demonstrated the effectiveness of human ASC/MSC infusion within a xenogeneic environment in murine models of lung injury [13,17,24,27,30,41], although the present study highlights for the first time the development of a short host immune response against the infused xenogeneic cells. Nevertheless, from a clinical standpoint, the immunemediated clearance of allogeneic hASCs, particularly genetically engineered hASCs, in the treated lungs should reduce the safety concerns regarding the persistence of these implanted cells longer than required.…”

Comparative Studies of Lymph Node Cell Subpopulations and Cytokine Expression in Murine Model for Testing the Potentials of Chemicals to Induce Respiratory Sensitization

“…Using ELISA or mRNA expression techniques it has already been shown that cytokine production from cells of lymph nodes draining the site of chemical application for some chemicals shows specific profiles of synthesis that characterize processes of dermal or respiratory sensitization [8,27,28]. In our model, based on ELISA technique, we failed to show a specific profile of the cytokine production and found that both IL-4 as well as IFN-γ were increased after in vitro lymph node cell stimulation [42]. These analyses were confirmed in our present study and reported by other authors previously [17].…”

Skin Exposure and Asthma: Is There a Connection?

“…Studies in mice, rats, and rabbits with the three major isocyanates (TDI, MDI, HDI) have demonstrated that isocyanate skin exposure can induce systemic Th2-like sensitization and subsequent airway inflammation when followed by inhalation challenge (11)(12)(13)(14)(15). These studies have demonstrated that dose, route, and timing of the sensitizing dose are key determinants of sensitization and subsequent asthma.…”