MHV-1 is a -coronavirus like SARS-CoV-2, but it can be studied under BSL-2 conditions. Because these two viruses are related, have many structural similarities and functional similarities including pneumonia with inflammatory lung injury and hypoxemia as well as systemic changes (e.g. lymphopenia, thrombocytopenia and thrombotic changes) over a time course similar to SARS-CoV-2, MHV-1 can be used to investigate treatments for SARS-CoV-2 infection (COVID-19). Oxygen is required for normal cellular metabolism. Oxygen therapy, also known as supplemental oxygen, is the use of oxygen as medical treatment, particularly for the patients with hypoxia. It first became common around 1917, and is the most common hospital treatment now. However, excessively high concentrations or fraction of inspired oxygen (FiO2) >0.6 can result in oxygen toxicity, leading to lung damage and respiratory failure. As opposed to these harmful inflammatory effects in high FiO2, FiO2s of 0.21 to 0.60 are believed to have limited toxic effects and are routinely used therapeutically to prevent hypoxemia in patients with pneumonia. Prolonged courses of FiO2s in this range have been used for many patients with SARS-CoV-2 pneumonia (COVID-19). However, in our mouse model of MHV-1 pneumonia which closely simulates the inflammatory tissue injury and time course of early SARS-CoV-2 pneumonia, FiO2s in this therapeutic range had no clear beneficial survival effect and, dependent on its timing and level, had significantly harmful ones. Compared to FiO2=0.21, FiO2=0.30 started 2h after intratracheal MHV-1 inoculation significantly worsened survival and when delayed until 48 and 72h after inoculation only produced a nonsignificant survival effect on the side of benefit. An FiO2=0.60 worsened survival significantly whether it was started early or up to 96h after challenge. These findings, with FiO2s frequently employed in COVID-19 patients, were unexpected but raise the possibility that the robust inflammatory response associated with MHV-1 may augment the potentially toxic effects of even low levels of oxygen support. This possibility has been speculated to occur in SARS-CoV-2 patients but cant be studied clinically due to the universal use of oxygen and no clinical trial testing the effect of oxygen therapy vs non-oxygen therapy in the hypoxic patients. We hypothesize that pathways involving hypoxia inducible factors, which we have explored before in this model, and reactive oxygen species might be implicated in the mortality we observe. The present study will investigate with blood and tissue measures the pathogenic mechanisms underlying the limited beneficial effects and markedly harmful ones FiO2s of 30 and 60% had in this MHV-1 pneumonia model. Animals will be randomized to be challenged with intratracheal (IT) MHV-1 or diluent and then randomized again to be treated with FiO2 of 0.21 (i.e compressed room air using an air compressor, which is what was used in our prior studies with MHV-1), 0.30 or 0.60. Oxygen therapy will be started 48h after viral challenge, a time at which oxygen saturation levels significantly decreased in MHV-1 challenged animals and will be continued through the end of study. The study will be conducted using a factorial design to differentiate the effects of oxygen therapy and MHV-1 alone and together. Due to the small size of the mouse and the range of measures planned, the study will be conducted in several parts with each part directed at a particular set of measures. Survival experiments have been conducted and completed. We are currently in the data and tissue collection phase of the study. We have completed a systematic review of the literature evaluating studies that have assessed the effects of oxygen therapy at levels less than 60% on various outcomes, including death. This review is being prepared for submission. Limited preclinical studies have examined the effects of low but supraphysiologic FiO2s in inflammatory lung injury models: A systematic review and analysis. Samuel Minkove, Rhea Dhamapurkar, Xizhong Cui, Yan Li, Junfeng Sun, Diane Cooper, Peter Q. Eichacker, Parizad Torabi-Parizi