Trimellitic Anhydride-Induced Eosinophilia in a Mouse Model of Occupational Asthma

Abstract

Trimellitic anhydride (TMA) is a low-molecular-weight chemical known to cause occupational asthma. The present study was designed to determine if TMA elicited eosinophil infiltration into lungs of sensitized mice similar to previous studies with the protein allergen ovalbumin (OA). BALB/c mice were sensitized intradermally with 0.1 ml of 3% TMA or 0.3% OA in corn oil followed by intratracheal instillation with TMA conjugated to mouse serum albumin (TMA-MSA; 30 or 400 microg) or OA (30 microg). Nonsensitized mice received corn oil vehicle intradermally and MSA (30 microg) intratracheally. The allergic response was elicited 3 weeks later by intratracheal instillation of 30 or 400 microg TMA-MSA, OA, or control MSA. Cellular infiltration into bronchoalveolar lavage fluid (BAL) was determined 72 h later. Eosinophil peroxidase (EPO) and myeloperoxidase (MPO) activity in lung homogenates was used as an estimate of numbers of eosinophils and neutrophils, respectively, in lung tissue. In TMA-sensitized mice, TMA-MSA challenge significantly increased numbers of eosinophils in BAL and EPO in lung, indicating an increase in number of eosinophils in the airway and tissue. In nonsensitized mice, TMA-MSA challenge also caused a small but significant increase in eosinophils in BAL compared to MSA control. Total IgE in both plasma and BAL was significantly higher in TMA-sensitized compared to nonsensitized mice. The eosinophil infiltration in TMA-sensitized mice was similar in magnitude to the response in OA-sensitized mice. These studies are the first to demonstrate TMA-induced eosinophilia in mouse lung and to provide a model for comparing mechanisms and mediators responsible for the substantial eosinophilia induced by TMA and OA.

Assessment of Airway Sensitization Potential of Inhaled Trimellitic Anhydride by Monitoring the Elicitation Phase in a Mouse Model

“…Similar observations were obtained with animals in both the ID/ID and IH/IH groups in which neither Penh nor IgE values were significantly elevated. TMA concentration used for the intradermal sensitization was 3% according to the protocol by Regal et al (2001). As compared with the IgE values in the study of Regal et al, those in the ID/EP and ID/ID groups were not too different, indicating that the weak airway and lung responses in these groups were attributable to the lower total serum IgE values than those noted in the EP/EP hi group.…”

“…To our knowledge, this is for the first time to report disturbed respiration induced in mice during and after challenge with free TMA dust. As an alternative route to inhalation exposure at challenge, intranasal or intratracheal instillation of chemicals has also been employed (Ebino et al, 1998;Scheerens et al, 1999;Regal et al, 2001;Herrick et al, 2002;Larsen and Regal, 2002;Sailstad et al, 2003;Farraj et al, 2004;Vanoirbeek et al, 2004). There are, however, some limitations to real-time monitoring of physiological respiration patterns when using these methods.…”

“…A number of test methods using animal models have been developed for detection of, and research on, the sensitization potential of low molecular weight (LMW) chemicals (Buehler, 1965;Magnusson and Kligman, 1969;Gad et al, 1986;Karol, 1987;Botham et al, 1989;Arts et al, 1998;Regal et al, 2001;Herrick et al, 2002;Pauluhn, 2003;Vanoirbeek et al, 2004;Matheson et al, 2005). Among them, widely validated tests are those for skin sensitization, and even recently, the local lymph node assay (LLNA; Kimber et al, 1989) has been evaluated by the Interagency Coordinating Committee on the Validation of Alternative Methods (ICCVAM; Sailstad et al, 2001) and finally adopted in the test guidelines of USEPA and OECD.…”

Immunologic Effector Mechanisms in Animal Models of Occupational Asthma

“…Studies of Dearman et al (1996) and Plitnick et al (2002) have demonstrated that topical exposure to TMA in the mouse also results in elaboration of T H 2 cytokines such as IL-5. In examining the effector phase, intradermal sensitization with TMA and challenge with a TMA protein conjugate can result in eosinophilia in the Balb/c mouse that is accompanied by increased total IgE (Regal et al, 2001). Whether TMA sensitization and challenge results in airway hyperresponsiveness, mucus hypersecretion and airway remodeling in mouse models is unexplored.…”

“…In the guinea pig, administration of TMA dust to a nonsensitized animal can result in a bronchoconstriction and eosinophilia in the lung, with an even more pronounced effect in a sensitized animal (Larsen and Regal, 2002b). In the mouse, significant eosinophilia with TMA exposure has been documented even in the absence of prior exposure to TMA (Regal et al, 2001), again with a more pronounced eosinophilia in a sensitized animal. Clearly, TMA can lead to asthmatic symptoms in the absence of the specific immune response, and this can happen in parallel with specific immune-mediated pathways being operative.…”