Airway inflammation induced by reactive oxygen species-mediated activation of redox-sensitive transcription factors is the hallmark of asthma, a prevalent chronic respiratory disease. In various cellular and animal models, we have recently demonstrated that, in response to multiple stimuli, aldose reductase (AR) regulates the inflammatory signals mediated by NF-kappaB. Because NF-kappaB-mediated inflammation is a major characteristic of asthma pathogenesis, we have investigated the effect of AR inhibition on NF-kappaB and various inflammatory markers in cellular and animal models of asthma using primary human small airway epithelial cells and OVA-sensitized/challenged C57BL/6 mice, respectively. We observed that pharmacological inhibition or genetic ablation of AR by small interfering RNA prevented TNF-alpha- as well as LPS-induced apoptosis; reactive oxygen species generation; synthesis of inflammatory markers IL-6, IL-8, and PGE(2); and activation of NF-kappaB and AP-1 in small airway epithelial cells. In OVA-challenged mice, we observed that administration of an AR inhibitor markedly reduced airway hyperresponsiveness, IgE levels, eisonophils infiltration, and release of Th2 type cytokines in the airway. Our results indicate that AR inhibitors may offer a novel therapeutic approach to treat inflammatory airway diseases such as asthma.