CNP-miR146a Mitigates Methicillin-Resistant Staphylococcus aureus–Induced Acute Lung Injury by Decreasing Inflammation

Abstract

INTRODUCTION: ARDS has a nearly 40% in-hospital mortality, and current treatment is largely limited to supportive care. Pneumonia and sepsis are the underlying causes responsible for ARDS in a majority of cases with inflammation as a central pathophysiologic feature. We have previously shown that CNP-miR146a, a radical scavenging cerium oxide nanoparticle (CNP) conjugated to the anti-inflammatory microRNA (miR)-146a, reduces bleomycin-induced acute lung injury by decreasing inflammation and oxidative stress. We therefore hypothesized that CNP-miR146a would decrease inflammation in methicillin-resistant Staphylococcus aureus (MRSA)–induced acute lung injury. METHODS: C57BL/6 mice (n = 46) were given IT MRSA or saline (control) followed 4 hours later by 1 ng/50 μL IT CNP-miR146a (MRSA + CNP-miR146a) or saline (control, MRSA). At 24 hours after infection, bronchoalveolar lavage fluid was analyzed by ELISA for proinflammatory cytokines. Whole lungs were processed for total RNA extraction, and quantitative polymerase chain reaction analysis was performed to evaluate proinflammatory gene expression. Statistical significance was determined by 1-way ANOVA (p < 0.05 significant). RESULTS: MRSA-injured lungs had significantly higher relative gene expression of proinflammatory IL-8 (p = 0.0056), IL-1β (p = 0.0023), and TNFα (p = 0.0024) compared with controls. Treatment with CNP-miR146a significantly lowered the expression of IL-6 (p = 0.0271), IL-8 (p = 0.0232), IL-1β (p = 0.0499), and TNFα (p = 0.0121). MRSA injury also significantly increased bronchoalveolar lavage fluid IL-6 protein concentration (p = 0.0011) compared with control, and treatment with CNP-miR146a returned this to control levels (p = 0.0227; Figure).Figure.: CNP-miR146a, a radical scavenging cerium oxide nanoparticle conjugated to the anti-inflammatory microRNA-146a; MRSA, methicillin-resistant Staphylococcus aureus.CONCLUSION: CNP-miR146a rescues the MRSA-injured lung by decreasing inflammation and bronchoalveolar proinflammatory protein leak, and therefore has significant promise as a potential therapeutic for ARDS.