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Covalent Binding, Protein leads to Increased proinflammatory mediators
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Covalent Binding of Low Molecular Weight Organic Chemicals to Proteins leads to Sensitisation (Sensitization) of the Respiratory Tract||adjacent||High||Not Specified||Arthur Author (send email)||Under Development: Contributions and Comments Welcome||Under Development|
Life Stage Applicability
Key Event Relationship Description
Covalent binding to proteins by electrophiles generates haptenated proteins which result in measurable increases in . As such, the induction and/or activation of a variety of proinflammatory mediators is a measurable result of stressors that covalently bind proteins.
Evidence Supporting this KER
Uncertainties and Inconsistencies
To elucidate which pathways respiratory sensitizers regulate, in vitro DNA microarray studies were performed in different human lung cell lines exposed to a limited set of respiratory sensitizers. These studies were not able to identify specific molecular pathways that were regulated by respiratory sensitizers. They could identify activation of genes, related to innate immune response. In human alveolar epithelial cells (A549 cell line), for example, genes encoding for TLR2, TNF-a, IL-1 receptor, and cytokine signaling pathways were upregulated by hexamethylene diisocyanate (HDI) and TMA. (Verstraelen et al., 2009) NLRP3 has been demonstrated to be important in respiratory sensitization by proteins, (Besnard et al., 2012) but the involvement in the induction of respiratory sensitization by low-molecular-weight chemicals is unknown. In human keratinocytes, the respiratory sensitizers MDI and TMA failed to elevate intracellular proinflammatory IL-18 levels. (Corsini et al., 2009) Conflicting reports as to whether IL-18 is associated with a Th1 or Th2 immune response hamper interpretation of this result.
Additionally, the canonical phosphatase and tensin homolog (PTEN)-signaling pathway might be relevant for respiratory sensitization. (Verstraelen et al., 2009) This pathway regulates cell survival signaling pathways and plays a protective role in the pathogenesis of asthma. (Kwak et al., 2003) In a mouse model of TDI-induced asthma, the PTEN pathway was shown to play a protective role in asthma pathogenesis, because it was involved in the regulation of IL-17 induction and NF-kB activation. (Kim et al., 2007) A more recent in vitro study showed that the PTEN pathway was not consistently induced by all respiratory sensitizers, since maleic anhydride and 7-aminocephalosporanic acid failed to induce this pathway but another diisocyanate, HDI, did. (Remy et al., 2014)
Haptenation is essentially instantaneous, and inflammatory responses to haptenated proteins are rapid. As a result, in vitro cytokine/chemokine secretion and redox responses may be quantifiable within minutes to a few hours, but sensitivity and precision vary based on the assay detection method. Haptenated peptides generated in vitro can be quantified after 15 minutes. (Hettick, et al., 2009) Most in vitro cellular assay protocols quantify inflammatory readouts after 24 – 48 hours of exposure.
Known modulating factors
Respiratory sensitizers without intrinsic electrophilic activity have been observed, and this is attributed to in situ generation of electrophilic activity. Pre-haptens and pro-haptens are converted from inactive molecules into active electrophiles by UV light and metabolic enzymes, respectively. (Aptula et al., 2007)
(Taylor et al;, 2020) found that single nucleotide polymorphisms (SNPs) in genese regulating inflammation, calcium regulation and endothelial function, and serine/threonine protein kinsase signaling were associated with differences in plasma and urine levels of 1,6-hexamethylene diisocyanate monomer and 1,6-hexamethylene diisocyanate isocyanurate following occupational exposure.
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
AGIUS, R. M., ELTON, R. A., SAWYER, L. & TAYLOR, P. 1994. Occupational asthma and the chemical properties of low molecular weight organic substances. Occup Med (Lond), 44, 34-6.
AGIUS, R. M., NEE, J., MCGOVERN, B. & ROBERTSON, A. 1991. Structure activity hypotheses in occupational asthma caused by low molecular weight substances. Ann Occup Hyg, 35, 129-37.
APTULA, A. O., ROBERTS, D. W. & PEASE, C. K. 2007. Haptens, prohaptens and prehaptens, or electrophiles and proelectrophiles. Contact Dermatitis, 56, 54-56.
BESNARD, A. G., TOGBE, D., COUILLIN, I., TAN, Z., ZHENG, S. G., ERARD, F., LE BERT, M., QUESNIAUX, V. & RYFFEL, B. 2012. Inflammasome-IL-1-Th17 response in allergic lung inflammation. J Mol Cell Biol, 4, 3-10.
CORSINI, E., MITJANS, M., GALBIATI, V., LUCCHI, L., GALLI, C. L. & MARINOVICH, M. 2009. Use of IL-18 production in a human keratinocyte cell line to discriminate contact sensitizers from irritants and low molecular weight respiratory allergens. Toxicol In Vitro, 23, 789-96.
EMTER, R., ELLIS, G. & NATSCH, A. 2010. Performance of a novel keratinocyte-based reporter cell line to screen skin sensitizers in vitro. Toxicol Appl Pharmacol, 245, 281-90.
ENOCH, S. J., ROBERTS, D. W. & CRONIN, M. T. 2010. Mechanistic category formation for the prediction of respiratory sensitization. Chem Res Toxicol, 23, 1547-55.
HETTICK, J.M., RUWONA, T.B. & SIEGEL, P.D. 2009. Structural elucidation of isocyanate-peptide adducts using tandem mass spectrometry. J Am Soc Mass Spectrom 20, 1567–1575.
HUANG, S., WISZNIEWSKI, L., CONSTANT, S. & ROGGEN, E. 2013. Potential of in vitro reconstituted 3D human airway epithelia (MucilAir™) to assess respiratory sensitizers. Toxicol In Vitro, 27, 1151-6.
HUR, G. Y., KIM, S. H., PARK, S. M., YE, Y. M., KIM, C. W., JANG, A. S., PARK, C. S., HONG, C. S. & PARK, H. S. 2009. Tissue transglutaminase can be involved in airway inflammation of toluene diisocyanate-induced occupational asthma. J Clin Immunol, 29, 786-94.
JOHANNESSON, G., ROSQVIST, S., LINDH, C. H., WELINDER, H. & JÖNSSON, B. A. 2001. Serum albumins are the major site for in vivo formation of hapten-carrier protein adducts in plasma from humans and guinea-pigs exposed to type-1 allergy inducing hexahydrophthalic anhydride. Clin Exp Allergy, 31, 1021-30.
KIM, S. R., LEE, K. S., PARK, S. J., MIN, K. H., LEE, K. Y., CHOE, Y. H., LEE, Y. R., KIM, J. S., HONG, S. J. & LEE, Y. C. 2007. PTEN down-regulates IL-17 expression in a murine model of toluene diisocyanate-induced airway disease. J Immunol, 179, 6820-9.
KIMBER, I., POOLE, A. & BASKETTER, D. A. 2018. Skin and respiratory chemical allergy: confluence and divergence in a hybrid adverse outcome pathway. Toxicol Res (Camb), 7, 586-605.
KWAK, Y. G., SONG, C. H., YI, H. K., HWANG, P. H., KIM, J. S., LEE, K. S. & LEE, Y. C. 2003. Involvement of PTEN in airway hyperresponsiveness and inflammation in bronchial asthma. J Clin Invest, 111, 1083-92.
LALKO, J. F., KIMBER, I., DEARMAN, R. J., API, A. M. & GERBERICK, G. F. 2013. The selective peptide reactivity of chemical respiratory allergens under competitive and non-competitive conditions. J Immunotoxicol, 10, 292-301.
LALKO, J. F., KIMBER, I., DEARMAN, R. J., GERBERICK, G. F., SARLO, K. & API, A. M. 2011. Chemical reactivity measurements: potential for characterization of respiratory chemical allergens. Toxicol In Vitro, 25, 433-45.
LAUENSTEIN, L., SWITALLA, S., PRENZLER, F., SEEHASE, S., PFENNIG, O., FÖRSTER, C., FIEGUTH, H., BRAUN, A. & SEWALD, K. 2014. Assessment of immunotoxicity induced by chemicals in human precision-cut lung slices (PCLS). Toxicol In Vitro, 28, 588-99.
NATSCH, A., RYAN, C. A., FOERTSCH, L., EMTER, R., JAWORSKA, J., GERBERICK, F. & KERN, P. 2013. A dataset on 145 chemicals tested in alternative assays for skin sensitization undergoing prevalidation. J Appl Toxicol, 33, 1337-52.
REMY, S., VERSTRAELEN, S., VAN DEN HEUVEL, R., NELISSEN, I., LAMBRECHTS, N., HOOYBERGHS, J. & SCHOETERS, G. 2014. Gene expressions changes in bronchial epithelial cells: markers for respiratory sensitizers and exploration of the NRF2 pathway. Toxicol In Vitro, 28, 209-17.
SEED, M. & AGIUS, R. 2010. Further validation of computer-based prediction of chemical asthma hazard. Occup Med (Lond), 60, 115-20.
SEED, M. J. & AGIUS, R. M. 2017. Progress with Structure-Activity Relationship modelling of occupational chemical respiratory sensitizers. Curr Opin Allergy Clin Immunol, 17, 64-71.
TAYLOR, L. W., FRENCH, J. E., ROBBINS, Z. G., BOYER, J. C. & NYLANDER-FRENCH, L. A. 2020. Influence of Genetic Variance on Biomarker Levels After Occupational Exposure to 1,6-Hexamethylene Diisocyanate Monomer and 1,6-Hexamethylene Diisocyanate Isocyanurate. Front Genet, 11, 836.
VERSTRAELEN, S., NELISSEN, I., HOOYBERGHS, J., WITTERS, H., SCHOETERS, G., VAN CAUWENBERGE, P. & VAN DEN HEUVEL, R. 2009. Gene profiles of a human alveolar epithelial cell line after in vitro exposure to respiratory (non-)sensitizing chemicals: identification of discriminating genetic markers and pathway analysis. Toxicol Lett, 185, 16-22.