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American Journal of Respiratory Cell and Molecular Biology. Vol. 27, pp. 385-390, 2002
© 2002 American Thoracic Society
DOI: 10.1165/rcmb.F249

Perspective

Mouse Models of Diisocyanate Asthma

Carrie A. Redlich, Adam V. Wisnewski and Terry Gordon

Occupational Medical Program and Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, Connecticut; Department of Environmental Medicine, New York University School of Medicine, Tuxedo, New York

Address correspondence to: Carrie A. Redlich, M.D., M.P.H., Yale University School of Medicine, 135 College St., New Haven, CT 06511. E-mail: carrie.redlich{at}yale.edu

Abbreviations: bronchoalveolar lavage, BAL • interleukin, IL • hexamethylene diisocyanate, HDI • matrix metalloproteinase, MMP • not reported, NR • polymorphonuclear neutrophil, PMN • subcutaneously, Sc • toluene diisocyanate, TDI • T helper, Th • tumor necrosis factor, TNF • vascular endothelial growth factor, VEGF.


   Introduction
Top
 Introduction
Clinical Presentation of...
 Pathogenesis of Diisocyanate...
 Animal Models of Diisocyanate...
 References
 
Occupational asthma is the most commonly reported occupational lung disease in many industrialized countries. Diisocyanates, highly reactive low molecular weight compounds used to make polyurethanes, are the most commonly identified cause of occupational asthma (1). Animal and clinical studies of diisocyanate asthma have been more limited compared with atopic asthma, and our understanding of diisocyanate pathogenesis is less clear. Unlike typical allergens that cause asthma, diisocyanates are extremely reactive compounds, creating great uncertainty regarding the carrier proteins for these chemical haptens in vivo. Research on diisocyanate asthma has been hampered by this uncertainty, as well as the lack of mouse models that replicate the human disease. Recent studies have made significant progress tackling both of these difficult problems. In the present issue of AJRCMB, Matheson and colleagues (2) investigate the role of tumor necrosis factor (TNF)-{alpha} in a mouse model of toluene diisocyanate (TDI) asthma. This Perspective will discuss these findings and address key issues that have hindered progress in understanding diisocyanate asthma and in developing better diagnostic tools. Several other recent promising mouse models that should facilitate future research are also discussed.

The major diisocyanates currently in use are diphenyl-methane diisocyanate, toluene diisocyanate, and hexamethylene diisocyanate (HDI) (Figure 1) . The characteristics of diisocyanate exposure that determine risk are unclear. Both the respiratory tract and skin are considered important routes of exposure and sensitization (3, 4). Depending on the specific diisocyanate, exposures can occur as an aerosol and/or as a vapor, as well as different monomeric and polymeric species, making airborne monitoring difficult (5). This complexity of exposure, along with the marked chemical reactivity, greatly adds to the difficulty of generating appropriate forms and concentrations of diisocyanates for use in animal models and in vitro studies.



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  		Figure 1. Chemical structure of the major commercial diisocyanates.

 

   Clinical Presentation of Diisocyanate Asthma
Top
 Introduction
 Clinical Presentation of...
Pathogenesis of Diisocyanate...
 Animal Models of Diisocyanate...
 References
 
Clinically, the presentation of diisocyanate asthma can be variable and difficult to distinguish from adult onset asthma due to other causes. There is a latency period between exposure and onset of symptoms; patients develop respiratory symptoms after recurrent exposures over months to a few years. Once sensitized, individuals can develop early, delayed, or dual asthmatic attacks in response to very low levels of exposure, making control difficult. Disease can persist away from exposure, emphasizing the importance of early diagnosis (6, 7). It is estimated that 5%–15% of exposed workers develop asthma (8, 9). However, exposure and host risk factors are not well understood. Unlike many types of asthma, atopy is not a risk factor for diisocyanate-induced disease. Certain human leukocyte antigen alleles and glutathione S-transferase haplotypes have been associated with diisocyanate asthma, but this has not been confirmed (10–12).

The diagnosis of diisocyanate asthma remains quite problematic and a challenge for physicians. Clinical history, questionnaires, and physiologic studies frequently are not definitive (13, 14). Immunologic tests, although of great interest, have shown variable correlation with disease. The prevalence of diisocyanate-specific IgG and IgE antibodies among individuals with diisocyanate asthma is variable and not closely associated with disease (13–18). Diisocyanate-specific lymphocyte proliferation or cytokine enhancement have also been investigated, but correlation with disease has been variable (19–21). A promising study by Bernstein and colleagues recently reported that monocyte chemoattractant protein-1 (MCP-1) in vitro production had a sensitivity 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 neither 100% sensitive nor specific, nor is it readily available (14, 22). Prevention is thus difficult due to the lack of diagnostic tests for sensitization or early disease, uncertainty regarding risk factors, as well as widespread and inherently difficult to control occupational exposures.


   Pathogenesis of Diisocyanate Asthma
Top
 Introduction
 Clinical Presentation of...
 Pathogenesis of Diisocyanate...
Animal Models of Diisocyanate...
 References
 
How diisocyanates cause airway inflammation and asthma remain poorly defined, hampering diagnostic and preventive strategies. Hypothesized mechanisms are summarized in Figure 2 . Recent studies have demonstrated that diisocyanates can become conjugated to specific human proteins, which then likely act as relevant diisocyanate antigens (23–25). A limited number of diisocyanate-conjugated proteins and peptides have been identified following in vivo exposure, including albumin, keratin, tubulin, and glutathione, all abundant in the respiratory tract and/or skin, the two primary sites of exposure (23–28). Most animal and in vitro human studies to date have used albumin as the carrier protein, based primarily on availability. A better understanding of biologically relevant diisocyanate antigens should greatly facilitate studies investigating diisocyanate asthma.



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  		Figure 2. Hypothetical model of the immunopathogenesis of diisocyanate asthma.

 
Many features of diisocyanate asthma are similar to atopic asthma, including airway inflammation characterized by activated CD4+ T cells, eosinophils and mast cells, airway remodeling, and increased levels of IL-4 and IL-5 (29–31). However, substantial differences have also been noted. More prominent airway neutrophilia, increased IL-8, TNF-{alpha}, and MCP-1 production, mixed Th1/Th2 cytokine responses, and relatively fewer eosinophils in patients with diisocyanate asthma have been reported, and suggest a more Th1-like environment and/or the involvement of CD8+ T cells (16, 32–34). Also notable is the low prevalence of diisocyanate-specific IgE antibodies among individuals with diisocyanate asthma (5%–20%) and the lack of association with atopy (9, 35).


   Animal Models of Diisocyanate Asthma
Top
 Introduction
 Clinical Presentation of...
 Pathogenesis of Diisocyanate...
 Animal Models of Diisocyanate...
References
 
Murine models have been widely used to study atopic asthma. Mouse ovalbumin models have successfully duplicated many features of atopic asthma: eosinophilic airway inflammation, Th2 T cell responses, and airway hyperresponsiveness, and have greatly contributed to our understanding of the immune mechanisms in atopic asthma (36). Animal models of diisocyanate asthma have been much more limited. Studies, most commonly in guinea pigs, have demonstrated the acute inhalational toxicity and immunogenicity of diisocyanates, as well as features characteristic of human asthma, including airway inflammation, airway hyperresponsiveness, and mucus hypersecretion following sensitization and respiratory tract exposure (37–45). These studies have also demonstrated that diisocyanates are acute irritants at higher doses, and that both skin and respiratory exposure can lead to sensitization and immune responses (3, 43, 46).

More mechanistic studies have been limited by the lack of a widely accepted mouse model that replicates human diisocyanate asthma. Mouse models are well known to offer numerous advantages, including the availability of genetically manipulated strains and a wide array of diagnostic reagents. Several mouse models have recreated the allergenicity of diisocyanates, including diisocyanate-specific IgE and contact hypersensitivity (47–50). However, it has been difficult to evoke diisocyanate-induced airway inflammation in mice, potentially related to poor delivery of the highly reactive diisocyanates to the lower airways, as well as difficulties measuring airway hyperresponsiveness in mice. Recently, several different promising mouse models have been developed (summarized in Table 1) (2, 51–57). These models vary greatly in regard to mice strain, the diisocyanate used, the route, timing, and dosing of diisocyanate sensitization and challenge, as well as the inflammatory and physiologic responses noted.


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  		TABLE 1 Selected murine models of diisocyanate asthma

 
In the present issue, Matheson and colleagues (2) investigate the role of TNF-{alpha} in a recently developed TDI mouse model involving sensitization by subcutaneous injection with liquid TDI and challenge by inhalation with TDI vapors, resulting in the production of TDI-specific IgG antibodies, upper respiratory tract (nasal and tracheal) inflammation, predominantly neutrophilic inflammation in the bronchoalveolar lavage (BAL) fluid, and airway hyperresponsiveness. Increased levels of airway IL-4 and TNF-{alpha} mRNA, and migration of airway dendritic cells to the draining lymph nodes were specifically documented (2). These TDI-induced responses were markedly reduced in TNF receptor double knockout mice and by treatment with neutralizing antibodies to TNF in wild-type mice; the exceptions were serum IgE and TDI-specific IgG levels, which remained elevated despite the other diminished immune responses to TDI (2). The authors conclude that TNF-{alpha} plays an important role in TDI-mediated immune events, which are distinct from the humoral antibody responses. The data may help explain the well-recognized lack of association between diisocyanate-specific antibody responses and asthma in occupationally exposed workers. Similar to other studies, airway inflammation has typically been difficult to replicate in diisocyanate-exposed mice, with most studies showing minimal lower airway inflammation or predominantly neutrophilic infiltrates. The upper airway inflammation and airway hyperresponsiveness noted is of interest, especially given the growing evidence that the upper and lower respiratory tract inflammatory responses are tightly linked, sharing common inflammatory features and mechanisms (58–60).

Several other groups have recently reported mouse TDI asthma models notable for airway hyperresponsiveness and/or lung inflammation. Lee and colleagues have investigated the role of matrix metalloproteinase (MMP) and vascular endothelial growth factor (VEGF) in a different mouse model of TDI asthma (52, 53). Intranasal sensitization with TDI followed by respiratory challenge with ultrasonically nebulized TDI resulted in airway hyperresponsiveness, inflammatory infiltrates around the bronchioles, a predominantly neutrophilic response in the BAL, and increased expression of MMP-9 and VEGF in the airway. Administration of MMP or VEGF inhibitors reduced these pathophysiologic changes, leading the authors to conclude that both MMP-9 and VEGF are important determinants of TDI asthma (52, 53). Of note, lung inflammation was a more prominent feature of this model, potentially related to a different TDI sensitization and/or higher dose challenge protocol. These studies also highlight the potential importance of mediators in addition to the more traditional Th2 T cells and chemokines that have been more extensively investigated in asthma pathogenesis.

Our collaborators, Herrick and colleagues, have recently published a mouse model of HDI asthma (51), developed as part of an interdisciplinary project integrating clinical, epidemiologic, and immunologic studies on HDI-exposed auto body shop workers (21, 61, 62). BALB/c mice were epicutaneously sensitized with HDI followed by intranasal respiratory challenge with HDI-albumin, resulting in BAL eosinophilia, marked lung inflammation composed of lymphocytes and eosinophils in a predominantly perivascular and peribronchiolar distribution, mucus hypersecretion, and an HDI-specific antibody response. Both Th1-type (IFN-{gamma}) and Th2-type (IL-4, IL-5, and IL-13) cytokine levels were increased, a result that is consistent with clinical studies showing mixed Th1/Th2 responses in diisocyanate asthmatics (51). Of interest, the sensitizing dose of HDI was an important determinant of airway inflammation and HDI-specific antibody responses. Skin sensitization with low doses of HDI (0.1%) resulted in prominent airway inflammation but minimal HDI-specific antibodies, whereas sensitization with a higher dose of HDI (1.0%) resulted in more prominent antibody responses but minimal lung inflammation. The data replicate the weak association of diisocyanate-specific antibodies and asthma, and are consistent with the dissociation of antibody responses and airway inflammation noted by Matheson and colleagues in this issue (2).

The recent development of these different mouse models of diisocyanate asthma is an important advance in understanding the immune and inflammatory responses to diisocyanate exposure. These new models, which employ different diisocyanate sensitization and challenge protocols and produce a range of inflammatory and immune responses, should greatly facilitate the study of the effects of diisocyanate exposure on the respiratory tract. Multiple questions remain to be answered, including the determination of relevant diisocyanate antigens and routes of exposure, better characterization of the inflammatory cells and mediators responsible for diisocyanate sensitization and asthma, and identification of the genetic factors that regulate airway inflammation.

Although these mouse models of diisocyanate asthma all share features common with human diisocyanate asthma, none perfectly replicates real-life human diisocyanate exposures or the disease in humans, as is also true of mouse models of atopic asthma (63, 64). It is important that findings from these mouse models be integrated with clinical studies of subjects exposed to diisocyanate and those with asthma. These models will enable investigators to pursue specific insights gained from patient-oriented research that cannot ethically or practically be addressed in human studies, and address some of the pressing clinical questions. A better understanding of the immunopathogenesis of diisocyanate asthma will hopefully lead to early markers of sensitization and asthma, as well as a better understanding of exposure and host risk factors, both of which should greatly facilitate the development of much-needed diagnostic and preventive strategies for diisocyanate asthma.


   Acknowledgments
 
One author (C.A.R.) is a recipient of an NIH K24 award (ES 00355).

Received in original form August 26, 2002


   References
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 Clinical Presentation of...
 Pathogenesis of Diisocyanate...
 Animal Models of Diisocyanate...
 References
 

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