Molecular and biophysical basis for the disruption of lung surfactant function by chemicals

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

“…The biological plausibility and empirical evidence of the inhibition of lung surfactant function by inhaled substances or by blood components reaching the alveolar airspaces, are high. Studies have been conducted for a number of substances including airborne nanoparticles ( Chen et al, 2017 , Yang et al, 2018 , Larsen et al, 2020 ), airborne chemicals ( Da Silva et al, 2021 ), and biological components such as albumin, cholesterol meconium, and serum ( Zuo et al, 2006 , Lopez-Rodriguez et al, 2011 , Lopez-Rodriguez et al, 2012 , Lopez-Rodriguez et al, 2013 , Zhang et al, 2012 , Autilio et al, 2021 , Gómez-Gil et al, 2009 , Lugones et al, 2018 , Gunasekara et al, 2005 ). For impregnation spray products, the inhibition of lung surfactant function has been reported across multiple methods in vitro , such as the lung surfactant bioassay ( Sørli et al, 2018 ), the capillary surfactometer ( Sørli et al, 2016 ), the pulsating bubble surfactometer ( Tashiro et al, 1998 ), and the Langmuir trough ( Duch et al, 2014 , Larsen, et al, 2014 ).…”

In vitro prediction of clinical signs of respiratory toxicity in rats following inhalation exposure

“…These 17 chemicals were acquired at the highest available purity from Sigma-Aldrich, Denmark. Three of the chemicals were further studied to determine the mechanisms underlying lung surfactant function inhibition, for further details see Da Silva et al 2021 ( Da Silva et al, 2021b ). Information relating to the TGs outcomes (both LC 50 and clinical observations) were provided by Firmenich or extracted from the available REACH registration dossiers.…”

“…1 jet nebulizer have an aerodynamic parameter below 5 µm, i.e. in the respirable range ( Sørli et al, 2015 , Sørli et al, 2018 , Larsen et al, 2020 , Da Silva et al, 2021b ). To ensure continuous air flow through the exposure chamber, the air was sucked out through the ventilation holes in the hollow baseplate.…”

“…In addition to affecting the assessment of dosimetry in the lung surfactant bioassay, the high volatility of certain compounds, and their fugacity capacity, can dictate their interaction with the lung surfactant. Other characteristics such as water solubility, boiling point (if very low) and hydrophobicity have been proposed to rule the molecular and biophysical disruption of lung surfactant function ( Da Silva et al, 2021b ). These parameters were not collected in the current study, but the chemical structure ( Table 2 in Supplementary Information ) indicates that they vary across the 26 test chemicals.…”

“…This correlated well with inhibition of lung surfactant function in vitro in the lung surfactant bioassay. At the molecular level, investigations of chemically-induced inhibition of the lung surfactant function identified that the test chemicals intercalated between the surfactant phospholipids at the air–liquid interface, reduced the stability of the lung surfactant films, and induced the loss of cohesivity of the multi-layered surfactant structures as the main perturbations ( Da Silva et al, 2021b ). At the organism level in humans, impregnation spray products that caused adverse respiratory outcomes after incidental exposure were also inhibitory to the lung surfactant function in vitro ( Duch et al, 2014 , Sørli et al, 2017 ).…”