Toluene diisocyanate (TDI) regulates haem oxygenase-1/ferritin expression: implications for toluene diisocyanate-induced asthma

Abstract

SummaryDiisocyanate is a leading cause of occupational asthma (OA). Diisocyanateinduced OA is an inflammatory disease of the airways that is associated with airway remodelling. Although the pathogenic mechanisms are unclear, oxidative stress may be related to the pathogenesis of diisocyanate-induced OA. In our previous report, we observed that the expression of ferritin light chain (FTL) was decreased in both of bronchoalveolar lavage fluid and serum of patients with diphenyl-methane diisocyanate (MDI)-induced OA compared to those of asymptomatic exposed controls and unexposed healthy controls. In this study of toluene diisocyanate (TDI)-OA, we found identical findings with increased transferrin and decreased ferritin levels in the serum of patients with TDI-OA. To elucidate whether diisocyanate suppresses FTL synthesis directly, we tested the effect of TDI on the FTL synthesis in A549 cells, a human airway epithelial cell line. We found that haem oxygenase-1 as well as FTL was suppressed by treatment with TDI in dose-and timedependent manners. We also found that the synthesis of other anti-oxidant proteins such as thioredoxin-1, glutathione peroxidase, peroxiredoxin 1 and catalase were suppressed by TDI. Furthermore, TDI suppressed nuclear translocation of Nrf2 through suppressing the phosphorylation of mitogenactivated protein kinases (MAPKs); extracellular-regulated kinase 1/2 (ERK1/ 2); p38; and c-Jun N-terminal kinase (JNK). Peroxisome proliferator-activated receptor-g (PPAR-g) agonists, 15-deoxy-D 12,14 -PGJ2 and rosiglitazone rescued the effect of TDI on HO-1/FTL expression. Collectively, our findings suggest that TDI suppressed HO-1/FTL expression through the MAPK-Nrf2 signalling pathway, which may be involved in the pathogenesis of TDI-induced OA. Therefore, elucidating these observations further should help to develop the therapeutic strategies of diisocyanate-induced OA.

Cells and mediators in diisocyanate-induced occupational asthma

“…Nrf2 regulates the expression of antioxidant enzymes, resulting in protection against toxicity following exposure to oxidative chemicals [85]. The reduction of heme oxygenase-1 levels was found to occur through the translocation of Nrf2, resulting in decreased Nrf2 and antioxidant responses following suppression of the phosphorylation of mitogen activated protein kinases after diisocyanates stimulation [17]. Another possible candidate is AMPactivated protein kinase (AMPK), which has been shown to inhibit production of cellular ROS through modulation of NADPH oxidase in human neutrophils [86].…”

“…TDI exposure was shown to induce permeability of AECs partly through the vascular endothelial growth factor (VEGF) pathway, which plays a crucial role in airway obstruction and hyperresponsiveness in TDI-induced asthma [11,12,13 && ]. In addition, diisocyanates induce oxidative stress by inducing reactive oxygen species (ROS) generation [14,15], which can induce epithelial cell inflammation by directly causing tissue injury [16] and altering various antioxidant systems, such as thioredoxin, glutathione, ferritin, and heme oxygenase-1 [17][18][19][20][21]. The imbalance between oxidant and antioxidant systems leads to the activation of the transcription factors activator protein-1 and NF-kB, which in turn mediate the production of proinflammatory mediators, such as TNF-a, interleukin (IL)-1, IL-8, and IL-6, from AECs [22].…”

Toluene Diisocyanate Reactivity with Glutathione Across a Vapor/Liquid Interface and Subsequent Transcarbamoylation of Human Albumin

“…A possible role for GSH in TDI asthma pathogenesis is suggested by several lines of evidence. In vitro studies with primary human bronchial cells, and in vivo mouse studies, have shown that TDI vapors can cause marked decreases in cellular thiol levels, and induce oxidative stress (10–14). Genetic studies in humans have shown an association of TDI asthma, and TDI metabolites in urine and serum, with specific GSH S-transferase polymorphisms (15–17).…”

La voie Nrf2 en pathologie respiratoire

“…Keap1 [28]. En revanche, il faut noter qu'un essai thérapeutique utilisant un inducteur de Nrf2 est en cours 1 .…”