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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.