Low-dose AgNPs reduce lung mechanical function and innate immune defense in the absence of cellular toxicity

Abstract

Multiple studies have examined the direct cellular toxicity of silver nanoparticles (AgNPs). However, the lung is a complex biological system with multiple cell types and a lipid-rich surface fluid; therefore, organ level responses may not depend on direct cellular toxicity. We hypothesized that interaction with the lung lining is a critical determinant of organ level responses. Here, we have examined the effects of low dose intratracheal instillation of AgNPs (0.05 µg/g body weight) 20 and 110nm diameter in size, and functionalized with citrate or polyvinylpyrrolidone. Both size and functionalization were significant factors in particle aggregation and lipid interaction in vitro. One day post-intratracheal instillation lung function was assessed, and bronchoalveolar lavage (BAL) and lung tissue collected. There were no signs of overt inflammation. There was no change in surfactant protein-B content in the BAL but there was loss of surfactant protein-D with polyvinylpyrrolidone (PVP)-stabilized particles. Mechanical impedance data demonstrated a significant increase in pulmonary elastance as compared to control, greatest with 110nm PVP-stabilized particles. Seven days post-instillation of PVP-stabilized particles increased BAL cell counts, and reduced lung function was observed. These changes resolved by 21 days. Hence, AgNP-mediated alterations in the lung lining and mechanical function resolve by 21 days. Larger particles and PVP stabilization produce the largest disruptions. These studies demonstrate that low dose AgNPs elicit deficits in both mechanical and innate immune defense function, suggesting that organ level toxicity should be considered.

Modulation of Human Macrophage Responses to Mycobacterium tuberculosis by Silver Nanoparticles of Different Size and Surface Modification

“…Additional characteristics of AgNP with gold core are discussed elsewhere by Botelho et al . [ 38 ].…”

Exposure to Silver Nanospheres Leads to Altered Respiratory Mechanics and Delayed Immune Response in an in Vivo Murine Model

“…Usually, metal NPs are stabilized by a “capping-agent” such as citrate or polyvinylpyrrolidone (PVP) (Bakshi et al, 2008 ; Leo et al, 2013 ). We have demonstrated previously that citrate-stabilized AgNPs elicit little biological response acutely in comparison to PVP-stabilized counterparts (Botelho et al, 2015 ). In this current study we use CB as a control for metal effects.…”

“…Our previous in vivo studies examining organ level toxicology of AgNPs (with gold cores) have demonstrated both size- and stabilization-dependent lung function effects (Botelho et al, 2015 ). Usually, metal NPs are stabilized by a “capping-agent” such as citrate or polyvinylpyrrolidone (PVP) (Bakshi et al, 2008 ; Leo et al, 2013 ).…”

Genetic determinants of susceptibility to silver nanoparticle‐induced acute lung inflammation in mice

“…AgNP studies in Sprague-Dawley (SD) rats provide additional evidence that size may also modify the timing of the inflammatory response and that size and coating affect the quantity and localization of AgNPs (17)(18)(19)(20). Furthermore, in C57BL/6 mice, size modified the dose response and timing of citrate-coated AgNP-induced lung inflammation, and surface coating and size altered AgNP effects on lung surfactant proteins and lung mechanics after instillation (10,21).…”

“…Additional strain differences included significant increases relative to control in total BALF protein and bronchial hyper-responsiveness in BN rats compared with SD rats after exposure to 20-nm citrate-and PVP-coated AgNPs. Thus, in vivo studies indicate that particle size, coating, and animal strain influence AgNP-induced lung inflammation and toxicity (10,12,(17)(18)(19)(20)(21).…”