Abstract
Acute exposure to ozone causes oxidative stress, characterized by increases in nitric oxide (NO) and other reactive nitrogen species in the lung. NO has been shown to modify thiols generating S-nitrosothiols (SNOs); this results in altered protein function. In macrophages this can lead to changes in inflammatory activity which impact the resolution of inflammation. As SNO formation is dependent on the redox state of both the NO donor and the recipient thiol, the local microenvironment plays a key role in its regulation. This dictates not only the chemical feasibility of SNO formation but also mechanisms by which they may form. In these studies, we compared the ability of the SNO donors, ethyl nitrite (ENO), which targets both hydrophobic and hydrophilic thiols, SNO-propanamide (SNOPPM) which targets hydrophobic thiols, and S-nitroso-N-acetylcysteine. (SNAC) which targets hydrophilic thiols. to modify macrophage activation following ozone exposure. Mice were treated with air or ozone (0.8 ppm, 3 h) followed 1 h later by intranasal administration of ENO, SNOPPM or SNAC (1-500 μM) or appropriate controls. Mice were euthanized 48 h later. Each of the SNO donors reduced ozone-induced inflammation and modified the phenotype of macrophages both within the lung lining fluid and the tissue. ENO and SNOPPM were more effective than SNAC. These findings suggest that the hydrophobic SNO thiol pool targeted by SNOPPM and ENO plays a major role in regulating macrophage phenotype following ozone induced injury.