ABSTRACT
Oxidative stress plays important roles in inflammatory responses during acute lung injury (ALI). Recently, nanoconstruct (Nano)-based drug-delivery systems have shown promise in many models of inflammation. In this study, we evaluated the anti-inflammatory effects of N-acetylcysteine (NAC) loaded in a biocompatible Nano using a rat model of ALI. We synthesized a Nano with a good NAC-releasing capacity using porous silica Nano, which was used to produce Nano/NAC complexes. For in vivo experiments, Sprague-Dawley rats were intraperitoneally administered NAC or Nano/NAC 30 min after intratracheal instillation of lipopolysaccharide. After 6 h, bronchoalveolar lavage fluids and lung tissues were collected. The anti-oxidative effect of the Nano/NAC complex was confirmed by demonstrating reduced levels of reactive oxygen species after treatment with the Nano/NAC in vitro. In vivo experiments also showed that the Nano/NAC treatment may protect against LPS-induced ALI thorough anti-oxidative and anti-inflammatory effects, which may be attributed to the inactivation of the NF-κB and MAPK pathways. In addition, the effects of Nano/NAC treatment were shown to be superior to those of NAC alone. We suggest the therapeutic potential of Nano/NAC treatment as an anti-inflammatory agent against ALI. Furthermore, our study can provide basic data for developing nanotechnology-based pharmacotherapeutics for ALI.
Subject(s)
Acute Lung Injury/drug therapy , Biocompatible Materials , Lipopolysaccharides/chemistry , Oxidative Stress , Animals , Anti-Inflammatory Agents/pharmacology , Antioxidants/pharmacology , Biotechnology/methods , Cytokines/metabolism , Drug Delivery Systems , Inflammation , Lung/metabolism , Male , Microscopy, Electron, Transmission , Nanoparticles , Nanotechnology/methods , Nitrogen , Rats , Rats, Sprague-Dawley , Reactive Oxygen SpeciesABSTRACT
NADPH oxidase (NOX) plays an important role in inflammatory response by producing reactive oxygen species (ROS). The inhibition of NOX has been shown to induce anti-inflammatory effects in a few experimental models. The aim of this study was to investigate the effects of diphenyleneiodonium (DPI), a NOX inhibitor, on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in a rat model. Sprague-Dawley rats were intraperitoneally administered by DPI (5 mg/kg) 30 minutes after intratracheal instillation of LPS (3 mg/kg). After 6 hours, bronchoalveolar lavage fluid (BALF) and lung tissue were collected. The NOX activity in lung tissue was significantly increased in LPS-treated rats. It was significantly attenuated by DPI. DPI-treated rats showed significant reduction in the intracellular ROS, the number of inflammatory cells, and cytokines (TNF-α and IL-6) in BALF compared with LPS-treated rats. In lung tissue, DPI-treated rats showed significantly decreased malondialdehyde content and increased activity of glutathione peroxidase and superoxide dismutase compared with LPS-treated rats. Lung injury score, myeloperoxidase activity, and inducible nitric oxide synthase expression were significantly decreased in DPI-treated rats compared with LPS-treated animals. Western blotting analysis demonstrated that DPI significantly suppressed LPS-induced activation of NF-κB and ERK1/2 and SAPK/JNK in MAPK pathway. Our results suggest that DPI may have protective effects on LPS-induced ALI thorough anti-oxidative and anti-inflammatory effects which may be due to inactivation of the NF-κB, ERK1/2, and SAPK/JNK pathway. These results suggest the therapeutic potential of DPI as an anti-inflammatory agent in ALI.
