Aggregation State of Metal-Based Nanomaterials at the Pulmonary Surfactant Film Determines Biophysical Inhibition

Abstract

Metal-based nanomaterials (MNMs) represent a large category of the engineered nanomaterials, and have been extensively used to enhance the electrical, optical, and magnetic properties of nanoenabled consumer products. Inhaled MNMs can penetrate deeply into the peripheral lung at which they first interact with the pulmonary surfactant (PS) lining of alveoli. Here we studied the biophysical inhibitory potential of representative MNMs on a modified natural PS, Infasurf, using a novel in vitro experimental methodology called the constrained drop surfactometry (CDS). It was found that the biophysical inhibitory potential of six MNMs on Infasurf ranks in the order CeO > ZnO > TiO > Ag > FeO > ZrO-CeO. This rank of in vitro biophysical inhibition is in general agreement with the in vitro and in vivo toxicity of these MNMs. Directly imaging the lateral structure and molecular conformation of the PS film using atomic force microscopy revealed that there exists a correlation between biophysical inhibition of the PS film by the MNMs and their aggregation state at the PS film. Taken together, our study suggests that the nano-bio interactions at the PS film are determined by multiple physicochemical properties of the MNMs, including not only well-studied properties such as their chemical composition and particle size, but also properties such as hydrophobicity, dissolution rate, and aggregation state at the PS film found here. Our study provides novel insight into the understanding of nanotoxicology and metallomics of MNMs.

Acute Inhalation Toxicity After Inhalation of ZnO Nanoparticles: Lung Surfactant Function Inhibition In Vitro Correlates With Reduced Tidal Volume in Mice

“…As opposed to aerosolizing ZnO NPs, others have mixed LS with ZnO NPs to evaluate the effect of LS function 30,31 also using the constrained drop surfactometer. Yang et al 31 studied the interaction of LS with several NPs, among which ZnO (mixed with the natural LS extract Infasurf to a final concentration of 10 µg/mg LS, or 1.2 cm 2 /mg).…”

“…As opposed to aerosolizing ZnO NPs, others have mixed LS with ZnO NPs to evaluate the effect of LS function 30,31 also using the constrained drop surfactometer. Yang et al 31 studied the interaction of LS with several NPs, among which ZnO (mixed with the natural LS extract Infasurf to a final concentration of 10 µg/mg LS, or 1.2 cm 2 /mg). The effects observed in the present study are much more severe at a lower exposure dose, where we observe an increase in minimum surface tension increases from 5.5 ± 0.6 to 13.8 ± 1.8 mN/m (n = 5) upon exposure, as opposed to an increase from 2.5 to 4.0 mN/m in the study by Yang et al 31 Yang et al showed that the rise of the minimum surface tension of Infasurf after exposure to ZnO NPs was directly correlated to alveolar collapse seen in histology and inflammation observed after intratracheal installation in mice.…”

An adverse outcome pathway for lung surfactant function inhibition leading to decreased lung function

“…The main advantages of this method include the accessibility of the air–liquid interface for exposure to airborne substances, flexibility in controlling cycling rates, and ease of determination of the surface tension in real-time while cycling the surfactant film. The constrained drop surfactometer has been applied to the exposure to a broad range of substances, including nanoparticles ( Larsen et al, 2020 , Valle et al, 2015 , Fan et al, 2011 , Yang et al, 2018 , Wang et al, 2020 ), individual chemicals ( Da Silva et al, 2021 ), mixtures of chemicals ( Da Silva, et al, 2021 , Sørli et al, 2018 , Sørli et al, 2016 ), excipients for drug formulation ( Sørli et al, 2018 ), per- and poly-fluoroalkyl substances ( Sørli et al, 2020 ), or plasma ( Autilio et al, 2021 ).…”

Adverse outcome pathways as a tool for the design of testing strategies to support the safety assessment of emerging advanced materials at the nanoscale

“…hydrophobic nanomaterials bind relatively more to phospholipids than hydrophilic nanomaterials [134]. A wide range of nanomaterials have been shown to affect the function of lung surfactant in vitro including metal and carbon-based nanomaterials [135][136][137][138][139][140][141][142][143].…”