Abstract Electronic-cigarette, or vaping, product use–associated lung injury (EVALI) has led to 2,758 hospitalized patients and has led to 52 deaths in the United States (CDC 2019). Most of the EVALI patients have a history of e- cigarette use or vaping and the majority report using tetrahydrocannabinol (THC) and vitamin E acetate containing products. Patients diagnosed with this illness have reported symptoms such as cough, shortness of breath or chest pain, nausea, vomiting or diarrhea, and fatigue, fever, or weight loss. The multiple causes and mechanisms of EVALI remain uncertain This proposal addresses the following major concerns about EVALI as outlined in the Notice of Special Interest: 1. What can we learn about mechanisms involved in the development of EVALI? 2. How do the agents in e-liquids, including thermal degradation products, affect the inflammatory state of pulmonary epithelia, endothelia, or immune cells? and 3. What aspects of EVALI pathology or biological response can be recapitulated and studied in cell or animal models of e-cigarette exposure? The aims of the proposal are: Aim 1. Deploy a comparative multi-omic analysis to determine the transcriptomic, metabolomic and proteomic signature of vitamin E acetate EVALI in mice. Mice will be exposed nose-only to a vaping device aerosols generated from vitamin E acetate, vitamin E, phenyl acetate, or phenol. Because pyrolysis of vitamin E acetate or phenyl acetate can generate ketene, a known toxicant, mice will also be exposed to ketene. Lungs and bronchoalveolar lavage will be assessed for evidence of EVALI. The results will be compared to our previous analysis of phosgene-, acrolein-, and chlorine-induced acute lung injury. Multi-omic analysis will be used to identify a differentially expressed signature (DES) for use with the LINCS L1000CDS 2 to identify agents/molecules that are predicted to perturb EVALI. This approach should identify potential means to prevent or attenuate EVALI. Aim 2. Obtain preclinical evidence for therapeutic intervention in EVALI. E-cigarette vapors consist of a mixture of particulates and gases including ketene and acrolein, which can generate carbonyl stress. Mice will be exposed to vitamin E acetate vapor and treated post-exposure with agents directed at carbonyl groups, hydralazine and phenelzine. In addition, two of the lead compounds identified by LINCS L10000CDS 2 will be evaluated. Bronchoalveolar lavage, histology, and DES will be assessed in mouse lung following EVALI. The outcome of this research will have substantial public health impact and will inform the ongoing investigation into this illness as well as its diagnosis, treatment, and prevention.