Abstract
BackgroundExposure to toluene diisocyanate (TDI) is a significant pathogenic factor for asthma. We previously reported that the receptor for advanced glycation end products (RAGE) plays a key role in TDI-induced asthma. Histone deacetylase (HDAC) has been reported to be important in asthmatic pathogenesis. However, its effect on TDI-induced asthma is not known. The aim of this study was to determine the role of RAGE and HDAC in regulating airway inflammation using a TDI-induced murine asthma model.MethodsBALB/c mice were sensitized and challenged with TDI to establish an asthma model. FPS-ZM1 (RAGE inhibitor), JNJ-26482585 and romidepsin (HDAC inhibitors) were administered intraperitoneally before each challenge. In vitro, the human bronchial epithelial cell line 16HBE was stimulated with TDI-human serum albumin (TDI-HSA). RAGE knockdown cells were constructed and evaluated, and MK2006 (AKT inhibitor) was also used in the experiments.ResultsIn TDI-induced asthmatic mice, the expression of RAGE, HDAC1, and p-AKT/t-AKT was upregulated, and these expressions were attenuated by FPS-ZM1. Airway reactivity, Th2 cytokine levels in lymph supernatant, IgE, airway inflammation, and goblet cell metaplasia were significantly increased in the TDI-induced asthmatic mice. These increases were suppressed by JNJ-26482585 and romidepsin. In addition, JNJ-26482585 and romidepsin ameliorated the redistribution of E-cadherin and β-catenin in TDI-induced asthma. In TDI-HSA-stimulated 16HBE cells, knockdown of RAGE attenuated the upregulation of HDAC1 and phospho-AKT (p-AKT). Treatment with the AKT inhibitor MK2006 suppressed TDI-induced HDAC1 expression.ConclusionsThese findings indicate that RAGE modulates HDAC1 expression via the PI3K/AKT pathway, and that inhibition of HDAC prevents TDI-induced airway inflammation.
Highlights
Toluene diisocyanate (TDI), a chemical used in many industries, and is a common cause of occupational asthma (OA)
receptor for advanced glycation end products (RAGE) inhibitor reduced expression of Histone deacetylase 1 (HDAC1) and AKT phosphorylation, and ameliorated airway inflammation in TDI‐induced asthmatic mice First, the expression of RAGE and HDAC1 was determined in each group
HDAC1 was mainly expressed in airway epithelium, with most of the immunostaining in the nucleus, while treatment with a RAGE inhibitor decreased HDAC1 expression (Fig. 1A)
Summary
Toluene diisocyanate (TDI), a chemical used in many industries, and is a common cause of occupational asthma (OA). RAGE is most highly expressed in lung tissue, and plays an important role in the pulmonary inflammatory response [3, 4]. It has been reported that RAGE is an important mediator of allergic inflammation and airway hyper-responsiveness (AHR) in house dust mite (HDM) and fungal extract-induced murine asthma models [5,6,7]. Our previous studies showed that the expression of RAGE and its ligands were increased in TDI-induced asthmatic mice, and that blocking the RAGE signal reduced airway inflammation [8,9,10]. We previously reported that the receptor for advanced glycation end products (RAGE) plays a key role in TDI-induced asthma. The aim of this study was to determine the role of RAGE and HDAC in regulating airway inflammation using a TDI-induced murine asthma model
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