Disruption of pulmonary resolution mediators contribute to exacerbated silver nanoparticle-induced acute inflammation in a metabolic syndrome mouse model
Introduction
Inhaled exposures can induce pulmonary inflammation, promoting the development of diseases such as asthma, fibrosis, chronic obstructive pulmonary disease (COPD), and others (Agarwal et al., 2020; Arias-Pérez et al., 2020; Klomp et al., 2021; Lotfi et al., 2020; Schett and Neurath, 2018; Utell and Samet, 1990). Inflammation is a coordinated process involving initiation and resolution allowing the immune system to respond to a variety of insults and return to homeostasis (Chen et al., 2018). Appropriate regulation of inflammation is necessary for the lung, due to constant interactions with the atmosphere and its sensitive alveolar structure. Inappropriate resolution can exacerbate and prolong the inflammatory processes and thus, may contribute to many exposure-related pulmonary diseases. Pulmonary inflammation is characterized by infiltration of immune cells (macrophages and neutrophils), goblet cell hyperplasia, and tissue damage resulting in increased epithelial permeability and edema (Leitch et al., 2008). Both initiation and resolution of inflammation are active processes regulated by lipid mediators (Serhan, 2010; Serhan and Petasis, 2011). Specifically, resolution is mediated via specialized pro-resolving mediators (SPMs) produced by metabolism of the ω-6 polyunsaturated fatty acid (PUFA) arachidonic acid to lipoxins and ω-3 PUFAs eicosatetraenoic acid (EPA) and docosahexaenoic acid (DHA) to resolvins, maresins, and protectins (Chiang and Serhan, 2020). SPMs promote resolution in a time-dependent manner and are highly potent functioning at the pico- to nanomolar level (Chiang and Serhan, 2020). Specifically, SPMs induce anti-inflammatory signaling, neutrophilic apoptosis, and macrophage clearance of apoptotic neutrophils, as well as initiate repair processes (Chiang and Serhan, 2020). Although not the focus of most toxicity assessments, exposures may impair the coordinated resolution of inflammation resulting in adverse effects. For instance, decreases in SPMs were determined following ozone inhalation contributing to pulmonary inflammation (Kilburg-Basnyat et al., 2018; Yaeger et al., 2021). Individual factors such as age, genetics, and underlying disease state may modulate resolution, resulting in increased susceptibility to inhaled exposures.
Pre-existing diseases can enhance susceptibility to environmental exposures, resulting in enhanced adverse effects (Sacks et al., 2011). Many diseases involve lipid dysregulation may impair the coordinated inflammation signaling following exposures. Metabolic syndrome (MetS) is a major health concern, affecting 34.2% of all U.S. adults, 50% of adults 60 years or older, and 9.8% of children (Moore et al., 2017). MetS consists of a combination of components including hypertension, hyperlipidemia, hyperglycemia, and increased waist circumference (Cornier et al., 2008). MetS predisposes individuals to serious chronic diseases such as Type 2 diabetes, cardiovascular disease, cancer, and others (Grundy et al., 2005). Evaluations of the National Health and Nutrition Examination Survey database in conjunction with the U.S. EPA's Aerometric Information Retrieval system demonstrated an increase of circulating white blood cells, indicative of enhanced inflammation, due to particulate matter exposure in those with MetS compared to healthy individuals (Chen and Schwartz, 2008). Furthermore, individuals with MetS exposed to dust at the World Trade Center exhibited diminished lung function compared to healthy individuals (Naveed et al., 2012; Weiden et al., 2013). Together these epidemiological assessments establish that individuals suffering from MetS are increasingly sensitive to inhaled exposures. However, the mechanisms responsible for these exacerbated inflammatory effects following inhalation exposures in MetS remain unknown. To date, most toxicity assessments are performed in healthy models limiting our knowledge of distinct toxicity mechanisms in susceptible populations such as MetS. This deficiency impairs effective public health protections for this prominent susceptible subpopulation.
Nanosized particulate matter composes a significant portion of air pollution and is associated with the development of many diseases including cardiopulmonary and metabolic diseases (Brook et al., 2010; Nemmar et al., 2013; Ning et al., 2021; Zhang et al., 2021). Engineered nanoparticles (NPs) represent a technology that is increasingly incorporated into applications, products, and procedures, enhancing environmental, occupational, consumer, and biomedical exposures (Kessler, 2011). Following inhalation, NPs efficiently deposit within the respiratory tract where they can cause toxicity, including inflammation, apoptosis, oxidative stress, damage to the epithelial air interface, fibrotic changes, and impaired pulmonary function in healthy models (Sharifi et al., 2012). Recently, we demonstrated that a mouse model of MetS exhibited enhanced acute pulmonary inflammation following silver NP (AgNP) exposure via oropharyngeal aspiration compared to healthy mice (Alqahtani et al., 2020). This enhanced inflammation corresponded with decreases in pulmonary SPMs suggesting diminished inflammatory resolution may contribute to susceptibility observed in MetS. Specifically, our lipid screening approach determined AgNP exposure significantly reduced the pulmonary levels of EPA, DHA, 18-HEPE, 17-HDHA, 14-HDHA, maresin-1, and a number of resolvins in the MetS model. These lipid alterations and the enhanced inflammatory response were resolved by treatment of MetS mice with atorvastatin. Together, these results suggest lipid dysregulation in MetS impairs resolution of inflammation following NP exposure exacerbating pulmonary inflammation. Statins have a number of immune effects that cause anti-inflammatory effects beyond lipid regulation (Jain and Ridker, 2005; Ota et al., 2010). Further, the contribution of distinct SPMs and their dysregulation to MetS-associated exacerbated inflammation is unelucidated. This information is necessary to understand susceptibility and formulate targeted interventional strategies.
In our current study, we hypothesize MetS-associated dysregulation of specific SPM classes differentially contribute to increased acute pulmonary toxicity via impairment of inflammatory resolution. To evaluate this hypothesis, healthy and MetS mouse models were treated with distinct SPM precursors (18-hydroxy eicosapentaenoic acid (18-HEPE), 14-hydroxy docosahexaenoic acid (14-HDHA), 17-hydroxy docosahexaenoic acid (17-HDHA), or saline (control) via intraperitoneal injection) to evaluate their ability to modulate AgNP-induced acute pulmonary inflammation. The precursors selected are metabolized to produce distinct types and classes of SPMs. Specifically, 14-HDHA is a precursor to maresin-1 (Colas et al., 2016; Dalli et al., 2013), 17-HDHA is a precursor to protectin D1 and the resolvin D series (Hansen et al., 2019; Hong et al., 2003; Serhan et al., 2006, Serhan et al., 2002), and 18-HEPE is a precursor to the resolvin E series (Duvall and Levy, 2016; Serhan and Levy, 2018). Following exposure, pulmonary SPM levels were assessed via a targeted mass spectrometry-based approach and alterations in inflammation and injury were assessed. Overall, this study determines the contributions of specific SPM classes that are dysregulated in MetS to enhanced inflammation and toxicity following inhalation exposures. This information can be directly applied to interventional approaches for the growing and susceptible MetS subpopulation.
Section snippets
AgNP characterization
Silver nanoparticles (AgNPs) coated with citrate and a diameter of 20 nm were purchased from NanoComposix (San Diego, CA, United States). AgNPs were characterized by assessment of hydrodynamic size, polydispersion, and ζ-potential at a concentration of 25 μg/mL in DI water (ZetaSizer Nano, Malvern) to verify manufacturer's specifications (n = 3).
Animals models, diet-induced metabolic syndrome, lipid treatment, and AgNP exposure
C57BL/6J male mice were obtained at 6 weeks of age from the Jackson Laboratory (Bar Harbor, ME, United States). Mice were randomly assigned to two main
Silver nanoparticle characterization
Citrate-coated silver nanoparticles (AgNPs) were characterized to verify manufacturer specifications. The AgNPs were determined to have a hydrodynamic size of 29.7 nm ± 1.1, polydispersion index of 0.23 ± 0.04, and a ζ-potential of −35.1 mV ± 2.6 (ZetaSizer Nano, Malvern) in DI water at a concentration of 25 μg/mL. These parameters are all reported as mean ± standard deviation (n = 3).
Mouse model characterization
After 14 weeks on either the healthy or HFWD diet, markers of metabolic syndrome including body weight (BW),
Discussion
Individuals suffering from chronic diseases are increasingly susceptible to inhaled particulate exposures, however, the toxicological mechanisms responsible remain unelucidated (Chen and Schwartz, 2008; Devlin et al., 2014; McCormack et al., 2015; Wagner et al., 2014). Many prevalent diseases such as metabolic syndrome (MetS) are characterized by lipid dysregulation which may facilitate exacerbated exposure-induced inflammatory responses. Recently we demonstrated via a lipid screening approach,
Ethics approval and consent to participate
All use of animals in this study was approved by the Purdue Animal Care and Use Committee.
Consent for publication
All authors have read and consent for publication of this manuscript.
Availability of data and material
All data will be made available according to the National Institutes of Health policies.
Funding
This work was funded by the National Institute of Environmental Health Sciences (NIEHS) grant R00/ES024392.
Authors' contributions
SA designed of the study, performed the experiments, analyzed, and interpreted data, wrote the manuscript; LX, AJ, CR, and JF performed experiments; JS designed the study, interpreted data, and performed experiments; All authors contributed to editing the manuscript.
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors would like to acknowledge the support of the Purdue Metabolite Profiling Facility for their assistance in generating the data presented within the manuscript.
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