Trimellitic anhydride (TMA) dust induces airway obstruction and eosinophilia in non-sensitized guinea pigs

Abstract

Trimellitic anhydride (TMA) causes asthma after a latency period of sensitization. In non-sensitized humans and animals, limited studies indicate that TMA exposure may also cause symptoms of asthma without a latency period. Our previous studies (J. Pharmacol. Exp. Ther. 296 (2001) 284) in a guinea pig model of TMA-induced asthma demonstrated that sensitization and the complement system were required for eosinophilia. TMA conjugated to guinea pig serum albumin (TMA-GPSA) was used to elicit the response. Since occupational exposure to TMA occurs by inhalation of dust, the present studies determined if exposure to TMA dust in a non-sensitized guinea pig elicited airway obstruction and inflammation, and whether a significantly greater response occurred after a latency period of sensitization. Guinea pigs were intradermally injected with either corn oil (non-sensitized animals) or 30% TMA (sensitized animals). Three weeks later they were challenged by intratracheal insufflation with 1 mg TMA dust or lactose dust (control) using a dry powder delivery device. Pulmonary resistance, dynamic lung compliance, mean arterial blood pressure and heart rate were monitored for 10 min. In non-sensitized guinea pigs, significant increases in pulmonary resistance and decreases in dynamic lung compliance and blood pressure occurred after TMA challenge. In sensitized animals, the same dose of TMA caused significantly greater effects compared to nonsensitized animals. In a separate experiment, cellular infiltration into the lung was determined 24 h after challenge with TMA dust or lactose dust. In both non-sensitized and sensitized animals, eosinophils in the lung tissue were increased after TMA dust challenge compared to controls. Thus, these studies suggest that the response in non-sensitized animals differs depending on whether TMA dust or TMA-GPSA is used to elicit the response. TMA dust elicits significant airway obstruction and eosinophilia in a non-sensitized animal, with even greater airway obstruction occurring in a sensitized animal.

A new house dust mite–driven and mast cell–activated model of asthma in the guinea pig

“…To verify that HDM challenge induces allergic activation of mast cells, we quantified the levels of HDM‐specific immunoglobulins following the first challenge and found that HDM‐treated guinea pigs were indeed sensitized to the allergen as shown by increased levels of HDM‐specific IgG 1 and IgG 2 compared with PBS‐treated guinea pigs. The induction of both IgG subclasses in response to allergens, including dust mites, has previously been described in guinea pigs 18,22‐24 . Furthermore, it has been shown that both immunoglobulins can induce the ASM contraction, 22,25 also in line with our study.…”

Trimellitic anhydride induces low-grade mast cell degranulation without specific IgE

“…A previous study revealed that TMA elicits significant airway obstruction and eosinophilia in a non-sensitized animal, and with even greater airway obstruction occurring in a sensitized animal [16] . Using animal model, it is shown that TMA induced typical morphological changes of the inflamed skin, strong infiltration with T cells, major histocompatibility complex positive cells, eosinophils, and mast cells, a T-helper cell-type 2 cytokine profile and strong increase of serum IgE levels [17] .…”

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

“…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.…”

“…Under these circumstances, since 1994, the Mouse IgE Test (MIGET; Kimber et al, 1996) and the Guinea Pig Test (GPT; Karol, 1983;Hayes et al, 1992;Larsen and Regal, 2002) have been recognized and recommended as the major airway sensitization tests by the European Center for Ecotoxicology and 98 UEDA ET AL.…”