Electronic cigarettes (ecigs) gained popularity in never- and active-smokers who are persuaded by intense ad campaigns that brands their use as a healthy alternative to cigarette smoke. Whether heated vaporized contents in ecigs, e.g., propylene glycol (PG), vegetable glycerol (VG) with or without nicotine, are safe alternatives to cigarette smoking remains unknown. We have developed a robust mouse model of conventional and ecig exposure and made several novel discoveries that provide unique insights into the toxicology of ecig in the lungs. In the first year of our funding, we have shown that the popular ecig solvents (e.g., 60/40 ratio of PG/VG), independent of nicotine, can alter lung lipid homeostasis and disrupt the function of alveolar macrophages and epithelial cells (Madison et al, JCI, 2019). We showed that ecig exposure can result in increased abundance of endogenous lipid species normally found in the lung lining fluid, but surfactant proteins (SP)-A, and SP-D associated with these lipids are significantly reduced. Several recent reports have described sporadic cases of ecig (nicotine, and/or cannabis) users who presented with a mysterious (non-infectious) type of lipoid pneumonia. These respiratory illnesses are clinically characterized by dyspnea, fatigue, and in most severe form, respiratory failure and death. Currently the causative factor(s) for the acute respiratory failure in ecig users remains unknown, however the FDA reported that over of the ecig liquid samples linked to the hospitalized patients tested positive for Vitamin E (Vit E) acetate. In this supplemental application, we request funding to examine the acute and chronic effects of Vit E acetate inhalation to determine whether they play a causative role in lung toxicity. We propose the following two Specific Aims: Aim 1. To determine the effect of acute and chronic inhalational exposure to Vitamin E acetate in mice. We have found that independent of nicotine, lung surfactant composition in mice exposed to chronic ecig is altered. The cannabis-containing ecig liquid used by a number of patients who presented with acute respiratory failure, contains Vit E acetate, a common solvent used in dermatological products. Using our well established ecig model, we will determine if acute (two weeks) or chronic (two months) exposure to Vit E acetate alone or in combination with PG/VG can alter surfactant in the lungs. Aim 2. To determine whether acute or chronic inhalation of Vitamin E acetate alters the function of macrophages and/or epithelial cells in the lungs. A common clinical feature of reported cases in several hundred ecig users who have presented with respiratory failure, is the diagnosis of lipoid pneumonia which is characterized by the presence of abnormal lung macrophages that contain large amounts of intracytoplasmic lipids. Given that Vit E acetate, has been found in ecig products used by over half of the cases associated with severe respiratory disease, we hypothesize that it can synergize with the common solvents in ecig to induce cellular toxicity in lung immune and or epithelial cells.