title: Cardiac Ischemia Reperfusion Injury Following Instillation of 20 nm Citrate-capped Nanosilver.
abstract: BACKGROUND
  Silver nanoparticles (AgNP) have garnered much interest due to their antimicrobial properties, becoming one of the most utilized nano-scale materials. However, any potential evocable cardiovascular injury associated with exposure has not been reported to date. We have previously demonstrated expansion of myocardial infarction after intratracheal (IT) instillation of carbon-based nanomaterials. We hypothesized pulmonary exposure to Ag core AgNP induces a measureable increase in circulating cytokines, expansion of cardiac ischemia-reperfusion (I/R) injury and is associated with depressed coronary constrictor and relaxation responses. Secondarily, we addressed the potential contribution of silver ion release on AgNP toxicity.
  
  
  METHODS
  Male Sprague-Dawley rats were exposed to 200 μl of 1 mg/ml of 20 nm citrate-capped Ag core AgNP, 0.01, 0.1, 1 mg/ml Silver Acetate (AgAc), or a citrate vehicle by intratracheal (IT) instillation. One and 7 days following IT instillation the lungs were evaluated for inflammation and the presence of silver; serum was analyzed for concentrations of selected cytokines; cardiac I/R injury and coronary artery reactivity were assessed.
  
  
  RESULTS
  AgNP instillation resulted in modest pulmonary inflammation with detection of silver in lung tissue and alveolar macrophages, elevation of serum cytokines: G-CSF, MIP-1α, IL-1β, IL-2, IL-6, IL-13, IL-10, IL-18, IL-17α, TNFα, and RANTES, expansion of I/R injury and depression of the coronary vessel reactivity at 1 day post IT compared to vehicle treated rats. Silver within lung tissue was persistent at 7 days post IT instillation and was associated with an elevation in cytokines: IL-2, IL-13, and TNFα and expansion of I/R injury. AgAc resulted in a concentration dependent infarct expansion and depressed vascular reactivity without marked pulmonary inflammation or serum cytokine response.
  
  
  CONCLUSIONS
  Based on these data, IT instillation of AgNP increases circulating levels of several key cytokines, which may contribute to persistent expansion of I/R injury possibly through an impaired vascular responsiveness.
authors.affiliation: Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA.
authors.forename: N A
authors.initials: NA
authors.lastname: Holland
authors.affiliation: Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Becak
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Shannahan
authors.affiliation: Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, The University of Colorado Anschutz Medical Campus, Aurora, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California at Davis, Davis, California, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Carratt
authors.affiliation: Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California at Davis, Davis, California, USA.
authors.forename: Lsv
authors.initials: L
authors.lastname: Winkle
authors.affiliation: Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California at Davis, Davis, California, USA.
authors.forename: K E
authors.initials: KE
authors.lastname: Pinkerton
authors.affiliation: Pacific Northwest National Laboratory, EMSL, Richland, USA.
authors.forename: C M
authors.initials: CM
authors.lastname: Wang
authors.affiliation: Pacific Northwest National Laboratory, EMSL, Richland, USA.
authors.forename: P
authors.initials: P
authors.lastname: Munusamy
authors.affiliation: Pacific Northwest National Laboratory, EMSL, Richland, USA.
authors.forename: Don R
authors.initials: DR
authors.lastname: Baer
authors.affiliation: RTI International, Discovery Sciences, Research Triangle Park, USA.
authors.forename: S J
authors.initials: SJ
authors.lastname: Sumner
authors.affiliation: RTI International, Discovery Sciences, Research Triangle Park, USA.
authors.forename: T R
authors.initials: TR
authors.lastname: Fennell
authors.affiliation: Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Lust
authors.affiliation: Department of Physiology, Brody School of Medicine at East Carolina University, Greenville, North Carolina, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Wingard
keywords: Coronary artery; Myocardial infarction; Nanotoxicology; Pulmonary exposure; Serum cytokines