The impact of vitamin E and its acetate derivative on lipid dynamics of unsaturated membrane systems

While α-tocopherol (αToc) is fundamentally recognized as a membrane-resident antioxidant, its synthetic derivative, α-tocopheryl acetate (αTocAc), has recently gained notoriety as a primary diluent in illicit vaping products associated with E-cigarette or Vaping Use-Associated Lung Injury (EVALI). The pathophysiology of EVALI has been linked to the disruption of pulmonary surfactant (PS) membranes, yet the specific impact on lipid dynamics and mechanical stability remains poorly defined. This study employs avoided level crossing muon spin resonance (ALC-μSR), quasielastic neutron backscattering (QENS), and neutron spin echo (NSE) to quantify the impacts of αToc and αTocAc on 1-palmitoyl-2-oleoyl-glycero-3-phosphocholine (POPC) and multicomponent PS mimic systems at a physiological temperature of 37 °C. ALC-μSR measurements reveal that αToc restricts local acyl chain dynamics, causing a 50% increase in the motionally averaged dipolar coupling that reduces the tail wobbling cone half-angle (θ_C). On a mesoscopic scale, QENS demonstrates that low concentrations (2-5 mol%) of αToc and αTocAc suppresses lateral lipid diffusivity (D_lat) in pure POPC from a baseline of 0.51×10^-10m²/s down to a minimum of 0.35×10^-10m²/s, following a non-monotonic trend that recovers near 10 mol%. Concurrently, NSE reveals a pronounced concentration-dependent stiffening of the fluid POPC bilayer, where αTocAc increases the bending modulus (κ) from a baseline of 17.9±0.7k_BT up to ≈31k_BT at 10 mol%, outstiffening the impact of its natural counterpart. Conversely, the unsaturated fraction of a complex PS mimic maintains a stable dynamic profile (D_lat≈0.35×10^-10m²/s), pointing to possible linactant compartmentalization at phase boundaries or clustering. Together, these multiscale findings establish a lipid-centric, biophysical mechanism for EVALI, where αTocAc restrict lateral lipid mobility and over-stiffen the fluid-phase reservoirs of the lung, fundamentally impeding the critical compression-expansion respreading mechanics of pulmonary surfactant required for normal respiration.