Intratracheal instillation of silver nanoparticles exacerbates cardiac ischemia/reperfusion injury in male sprague-dawley rats

Abstract

The uses of engineered nanomaterials have expanded in biomedical technology and consumer manufacturing. Exposure to particulate matter has been demonstrated to negatively influence cardiovascular health and expand myocardial infarction. Furthermore, pulmonary exposure to various engineered nanomaterials has, likewise, demonstrated the ability to exacerbate cardiac ischemia reperfusion (I/R) injury. We hypothesized that pulmonary exposure to AgNP induces cardiovascular toxicity in the form of expanded I/R injury, electrical dysfunction and inducing a persistent increase in circulating proinflammatory cytokines. To test this hypothesis, we exposed male SD rats to an intratracheal (IT) instillation of 200 µg of 20 or 110 nm polyvinylprryolidone (PVP) or citrate capped AgNP, in 200 ul of the respective PVP or citrate vehicle. Serum samples were collected prior to instillation and 1, 3, 6, 24, 48, 72, and 168 hours following instillation. Serum samples were analyzed by multiplex assay for concentrations of: G-CSF, GM-CSF, MIP-1a, IL -1b, IL-2, IL-5, IL-6, IL-10, IL-13, IL-17a, IL-18, MCP-1, IFNy, RANTES, and TNFa. Twenty four and 168 hours after IT exposure, cardiac ischemia was induced by left anterior descending coronary artery ligation for 20 minutes followed by 2 hours of reperfusion. Intraoperative ECG was monitored throughout cardiac I/R surgery for heart rate (HR), PR interval, and QT interval. To test the impact of silver ion exposure on cardiac I/R injury we administered 200 ul of 0.01 mg/mL, 0.1 mg/mL, or 1 mg/mL silver acetate (AgAc) and induced cardiac I/R 24 hours later. Intratracheal instillation of AgNP resulted in expansion of I/R injury for both sizes of citrate and PVP capped AgNP at both 24 hours and 168 following instillation; exposure to 0.1 and 1 mg/mL AgAc also resulted in expansion of I/R injury. Intratracheal instillation of AgNP did not result in increased serum concentrations of selected proinflammatory cytokines, however post I/R serum levels of IL-2, IL-6, and IL-18 were significantly elevated in rats exposed to 20 nm PVP capped AgNP compared to vehicle controls at 24 hours post instillation. Instillation of AgNP had no impact on HR or QT interval. However, exposure to 20 nm AgNP resulted in a differential prolongation or shortening of PR interval during reperfusion based on capping agent. In conclusion IT instillation of AgNP exacerbates cardiac I/R injury 24 and 168 hours following instillation, without inducing a strong systemic inflammatory response or electrical dysfunction. Exposure to AgNP may result in a sensitization of the immune system in response to a secondary insult (e.g., cardiac I/R) which are largely correlated with capping agents and particle size and may drive expansion of I/R injury at 24 and 168 hours following IT instillation of AgNP.