Registration is required for this free webinar
Hosted by the SOT Arab Toxicologists Association Special Interest Group & Inhalation and Respiratory Specialty Section
Nanoparticle (NP) safety evaluations have established the potential for inhalation toxicity and lung damage; however, they primarily utilize healthy models. Prevalent underlying diseases, such as metabolic syndrome (MetS), enhance susceptibility to inhaled exposures. Lipids are dysregulated in MetS and are intricately involved in inflammatory signaling facilitating both initiation and resolution. Specifically, our data demonstrate exacerbated acute, as well as sustained, pulmonary inflammation in a mouse model of MetS compared to a healthy model following 20nm silver NP exposure. Exacerbated MetS pulmonary inflammation corresponded with inhibition of numerous lipid resolution mediators. Therefore, we hypothesized modulation of pulmonary lipids could be utilized as a treatment strategy to address the exacerbated pulmonary inflammation in MetS following inhaled particulate exposures. Healthy and MetS mice were treated by incorporation of atorvastatin into their diet, exposed to 20nm silver NPs (50 μg), and evaluated for acute toxicity endpoints 24h post-exposure. Responses were compared to a cohort not receiving atorvastatin. Treatment with atorvastatin was determined to reduce exacerbated inflammation (neutrophilic influx and cytokine/chemokine levels) in MetS following NP exposure to levels observed in exposed healthy mice. An MRM profiling approach determined atorvastatin inhibited alterations in pulmonary lipid mediators of inflammatory resolution observed in MetS mice following NP exposure. These findings suggest lipid dysregulation may contribute to exacerbated toxicity associated with MetS. To examine the contribution of specific resolution mediators, a cohort of mice were treated with precursors of resolution mediators (14HDHA, 17HDHA, or 18HEPE) prior to NP exposure. Treatment with 14HDHA or 17HDHA prior to NP exposure was determined to reduce exacerbations in pulmonary neutrophilia in MetS mice while 18HEPE was ineffective. A targeted lipid assessment approach demonstrated treatments elevated distinct resolution mediators within the lung. Based on this data, healthy and MetS mice were exposed to NPs and treated with distinct mediators as treatments post-exposure. Treatments were determined to differentially reduce NP-induced pulmonary inflammation and accelerate resolution of inflammation. Overall, our evaluations suggest therapeutic targeting of lipid dysregulation may benefit individuals suffering from MetS exposed to inhaled toxicants by inhibiting exacerbated inflammatory responses.
Speaker
Jonathan Shannahan, PhD
Professor of Toxicology, School of Health Sciences, Purdue University