Occupational respiratory diseases induced by industrial chemicals are well documented. Among these diseases, asthma induced by low‑molecular‑weight agents such as isocyanates and acid anhydrides commonly used in manufacturing is characterized by dyspnea, chest tightness, and wheezing. We evaluated the effect of low‑molecular‑weight agents epidemiologically well‑established as associated with occupational asthma on normal or pathological states of the human airway epithelium using validated 3D-airway epithelial cell models. Treatment of MucilAir™, SmallAir™, and SmallAir-asthma™ models with methylene diphenyl diisocyanate (MDI), toluene diisocyanate (TDI), and trimellitic anhydride for 24 hours induced increased lactate dehydrogenase release and elicited morphologic alteration in the respiratory epithelium with characteristic cellular injury such as changes in the height of the epithelial cells, focal epithelial loss, and disorganization of the epithelium. Furthermore, histological modifications included epithelial hyperplasia, cyst formation and increased mucus secretion. We also examined reactive oxygen species as indicator of oxidative injury and profiled the cytokines, chemokines, and other markers of airway remodeling related to asthma pathogenesis. However, chemical exposure did not appear to induce concentration-dependent changes in reactive oxygen species, whereas MDI and TDI elicited alterations in interleukin (IL)-6, IL-1β, and IL-8 in SmallAir™ or SmallAir-asthma™ models. Although no meaningful alterations were observed in the parameters of oxidative damage or factors related with asthmatic mechanisms, likely due to methodological limitations, further investigation of 3D-cell airway models would support an advanced understanding of respiratory diseases, including asthma.

Abstract
INTRODUCTION
MATERIALS AND METHODS
    In vitro model of human respiratory epithelium
    Test chemicals
    Test conditions
    Cytotoxicity assay
    Measurement of reactive oxygen species and reactive nitrogen species
    Measurement of cytokines
    Histology
    Statistical analysis
RESULTS
    Cellular damage due to treatment with methylene diphenyl diisocyanate, toluenediisocyanate, and trimellitic anhydride
    Oxidative stress induced by chemicals
    Expression levels of asthma-related factors after chemical treatment
    Histological characteristics induced by chemicals
DISCUSSION
SUPPLEMENTARY MATERIALS
REFERENCES

• Eun-sang Cho(Inhalation Toxicity Research Center, Occupational Safety and Health Research Institute, Korea Occupational Safety and Health Agency (KOSHA), Daejeon 34122, Korea) Corresponding author