Low‐Dose Resveratrol Attenuates Toluene Diisocyanate‐Induced Steroid‐Resistant Asthma by Inhibiting HMGB1 Acetylation and Release

ABSTRACT Resveratrol (RES) has been shown to be a promising protective agent against asthma. However, its role in the steroid‐resistant asthma is unknown. Studies showed RES displayed hormetic action, protecting the cells at a lower dose while inducing cytotoxicity at higher doses, which limits its clinical application. In this study, we determined the efficacy of different doses of RES in a steroid‐resistant asthma model. A toluene diisocyanate (TDI)‐induced steroid‐resistant murine asthma model was established. The effects of different doses of RES were tested both in vitro and in vivo. We observed low‐doses RES (1, 10 mg kg −1 ) ameliorated TDI‐induced airway hyperresponsiveness, airway neutrophil accumulation, mucus production and collogen deposition as well as the release of Th2 and Th17‐related cytokines. Yet, the high‐dose RES (100 mg kg −1 ) had no protective effects. As a SIRT1 activator, RES expectedly increased pulmonary SIRT1 expression at doses of 1,10 and 100 mg kg −1 , but only low‐dose RES (1, 10 mg kg −1 in mice and 10 μM in vitro) decreased TDI‐induced bronchial epithelial HMGB1 acetylation, nucleocytoplasmic translocation and release. Further, we found pulmonary p300, a nuclear histone deacetyltransferase, significantly upregulated by TDI was suppressed by only low‐doses RES (1, 10 mg·kg −1 ). In addition, low‐dose rather than high‐dose RES attenuated TDI‐induced bronchial epithelial DNA damage and mitochondrial oxidative stress. Our data suggested that low‐dose RES inhibits HMGB1 acetylation and release and maintains SIRT1‐p300 balance, which ameliorates airway inflammation in TDI‐induced steroid‐resistant asthma.