Sulfur dioxide suppresses inflammatory response by sulfenylating NF-{kappa}B p65 at cysteine 38 in a rat model of acute lung injury

This study was designed to investigate whether endogenous sulfur dioxide (SO2) controlled pulmonary inflammation in a rat model of oleic acid (OA)-induced acute lung injury (ALI). In this model, adenovirus expressing aspartate aminotransferase (AAT) 1 was delivered to the lungs, and the levels of SO2 and pro-inflammatory cytokines in rat lung tissues were measured. In the human alveolar epithelial cell line A549, the nuclear translocation and DNA binding activities of wild-type (wt) and C38S NF-B p65 were detected. GFP-tagged C38S p65 was purified from HEK 293 cells, and the sulfenylation of NF-B p65 was studied. OA caused a reduction of SO2/AAT pathway activity but increased pulmonary inflammation and ALI. However, either the presence of SO2 donor, a combination of Na2SO3 and NaHSO3, or AAT1 overexpression in vivo successfully blocked OA-induced pulmonary NF-B p65 phosphorylation and consequent inflammation and ALI. Either treatment with an SO2 donor or overexpression of AAT1 downregulated OA-induced p65 activity, but AAT1 knockdown in alveolar epithelial cells mimicked OA-induced p65 phosphorylation and inflammation in vitro . Mechanistically, OA promoted NF-B nuclear translocation, DNA binding activity, recruitment to the ICAM-1 promoter, and consequent inflammation in epithelial cells; these activities were reduced in the presence of an SO2 donor. Furthermore, SO2 induced sulfenylation of p65, which was blocked by the C38S mutation on p65 in epithelial cells. Hence, do...
Source: Clinical Science - Category: Biomedical Science Authors: Tags: PublishAheadOfPrint Source Type: research