Mouse models of diisocyanate asthma.

Abstract

Occupational asthma is the most commonly reported ocpriate forms and concentrations of diisocyanates for use in animal models and in vitro studies. cupational lung disease in many industrialized countries. Diisocyanates, highly reactive low molecular weight comClinical Presentation of Diisocyanate Asthma pounds used to make polyurethanes, are the most commonly identified cause of occupational asthma (1). Animal Clinically, the presentation of diisocyanate asthma can be and clinical studies of diisocyanate asthma have been more variable and difficult to distinguish from adult onset asthma limited compared with atopic asthma, and our understanddue to other causes. There is a latency period between ing of diisocyanate pathogenesis is less clear. Unlike typical exposure and onset of symptoms; patients develop respiraallergens that cause asthma, diisocyanates are extremely tory symptoms after recurrent exposures over months to a reactive compounds, creating great uncertainty regarding few years. Once sensitized, individuals can develop early, the carrier proteins for these chemical haptens in vivo. Redelayed, or dual asthmatic attacks in response to very low search on diisocyanate asthma has been hampered by this levels of exposure, making control difficult. Disease can uncertainty, as well as the lack of mouse models that replipersist away from exposure, emphasizing the importance cate the human disease. Recent studies have made signifiof early diagnosis (6, 7). It is estimated that 5%–15% of cant progress tackling both of these difficult problems. In exposed workers develop asthma (8, 9). However, exposure the present issue of AJRCMB, Matheson and colleagues and host risk factors are not well understood. Unlike many (2) investigate the role of tumor necrosis factor (TNF)types of asthma, atopy is not a risk factor for diisocyanatein a mouse model of toluene diisocyanate (TDI) asthma. induced disease. Certain human leukocyte antigen alleles This Perspective will discuss these findings and address key and glutathione S-transferase haplotypes have been associissues that have hindered progress in understanding diisocyated with diisocyanate asthma, but this has not been conanate asthma and in developing better diagnostic tools. firmed (10–12). Several other recent promising mouse models that should The diagnosis of diisocyanate asthma remains quite facilitate future research are also discussed. problematic and a challenge for physicians. Clinical history, The major diisocyanates currently in use are diphenylquestionnaires, and physiologic studies frequently are not definitive (13, 14). Immunologic tests, although of great methane diisocyanate, toluene diisocyanate, and hexamethinterest, have shown variable correlation with disease. The ylene diisocyanate (HDI) (Figure 1). The characteristics of prevalence of diisocyanate-specific IgG and IgE antibodies diisocyanate exposure that determine risk are unclear. Both among individuals with diisocyanate asthma is variable and the respiratory tract and skin are considered important not closely associated with disease (13–18). Diisocyanateroutes of exposure and sensitization (3, 4). Depending on specific lymphocyte proliferation or cytokine enhancement the specific diisocyanate, exposures can occur as an aerosol have also been investigated, but correlation with disease and/or as a vapor, as well as different monomeric and polyhas been variable (19–21). A promising study by Bernstein meric species, making airborne monitoring difficult (5). This and colleagues recently reported that monocyte chemoatcomplexity of exposure, along with the marked chemical tractant protein-1 (MCP-1) in vitro production had a sensireactivity, greatly adds to the difficulty of generating approtivity and specificity of 79% and 91% in diagnosing diisocyanate asthma (16). Specific inhalation challenge is considered the “gold standard” for diagnosis. However, such testing is (Received in original form August 26, 2002) neither 100% sensitive nor specific, nor is it readily available