Immune sensitization to methylene diphenyl diisocyanate (MDI) resulting from skin exposure: albumin as a carrier protein connecting skin exposure to subsequent respiratory responses

Adam V Wisnewski,Carrie A Redlich,Eve Robinson,Lan Xu,Christina A Herrick,Jian Liu

doi:10.1186/1745-6673-6-6

Adam V Wisnewski, Carrie A Redlich + Show 4 more

Open Access

https://doi.org/10.1186/1745-6673-6-6

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Abstract

BackgroundMethylene diphenyl diisocyanate (MDI), a reactive chemical used for commercial polyurethane production, is a well-recognized cause of occupational asthma. The major focus of disease prevention efforts to date has been respiratory tract exposure; however, skin exposure may also be an important route for inducing immune sensitization, which may promote subsequent airway inflammatory responses. We developed a murine model to investigate pathogenic mechanisms by which MDI skin exposure might promote subsequent immune responses, including respiratory tract inflammation.MethodsMice exposed via the skin to varying doses (0.1-10% w/v) of MDI diluted in acetone/olive oil were subsequently evaluated for MDI immune sensitization. Serum levels of MDI-specific IgG and IgE were measured by enzyme-linked immunosorbant assay (ELISA), while respiratory tract inflammation, induced by intranasal delivery of MDI-mouse albumin conjugates, was evaluated based on bronchoalveolar lavage (BAL). Autologous serum IgG from "skin only" exposed mice was used to detect and guide the purification/identification of skin proteins antigenically modified by MDI exposure in vivo.ResultsSkin exposure to MDI resulted in specific antibody production and promoted subsequent respiratory tract inflammation in animals challenged intranasally with MDI-mouse albumin conjugates. The degree of (secondary) respiratory tract inflammation and eosinophilia depended upon the (primary) skin exposure dose, and was maximal in mice exposed to 1% MDI, but paradoxically limited in mice receiving 10-fold higher doses (e.g. 10% MDI). The major antigenically-modified protein at the local MDI skin exposure site was identified as albumin, and demonstrated biophysical changes consistent with MDI conjugation.ConclusionsMDI skin exposure can induce MDI-specific immune sensitivity and promote subsequent respiratory tract inflammatory responses and thus, may play an important role in MDI asthma pathogenesis. MDI conjugation and antigenic modification of albumin at local (skin/respiratory tract) exposure sites may represent the common antigenic link connecting skin exposure to subsequent respiratory tract inflammation.

Highlights

Methylene diphenyl diisocyanate (MDI), a reactive chemical used for commercial polyurethane production, is a well-recognized cause of occupational asthma
Skin exposure induces an MDI-specific antibody response The capacity of MDI skin exposure to induce an MDIspecific antibody response was evaluated through enzyme-linked immunosorbant assay (ELISA) analysis of sera from mice exposed to MDI diluted in acetone, at varying concentrations ranging from 0.1-10% weight/volume (w/v)
We found that skin exposure to ≥ 1% MDI resulted in the development of high serum levels of MDI-specific antibodies

Summary

Introduction

Methylene diphenyl diisocyanate (MDI), a reactive chemical used for commercial polyurethane production, is a well-recognized cause of occupational asthma. The major focus of disease prevention efforts to date has been respiratory tract exposure; skin exposure may be an important route for inducing immune sensitization, which may promote subsequent airway inflammatory responses. We developed a murine model to investigate pathogenic mechanisms by which MDI skin exposure might promote subsequent immune responses, including respiratory tract inflammation. Isocyanates, the reactive chemicals used in the production of polyurethane foams, coatings, and adhesives remain a leading cause of occupational asthma worldwide, despite substantial efforts at disease prevention [1]. The pathogenesis of MDI, and other isocyanate (TDI, HDI)-induced asthma remains unclear; contemporary theories suggest one important step involves the chemical’s reactivity with “self” proteins in the respiratory tract, causing antigenic changes in their structure/conformation, which trigger an immune response [10,11]. While the pathogenesis of MDI (and other isocyanate-induced) asthma remains unclear, previous studies support an important role for chemical conjugation with albumin present in the airways

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