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Studies have linked severe hyperoxia, or prolonged exposure to very high oxygen levels, with worse clinical outcomes. This study investigated the role of epidermal growth factor receptor (EGFR) in hyperoxia\u2010induced lung injury at very high oxygen levels (&gt;95%). <jats:italic>Results<\/jats:italic>. Effects of severe hyperoxia (100% oxygen) were studied in mice with genetically inhibited EGFR and wild\u2010type littermates. Despite the established role of EGFR in lung repair, EGFR inhibition led to improved survival and reduced acute lung injury, which prompted an investigation into this protective mechanism. Endothelial EGFR genetic knockout did not confer protection. EGFR inhibition led to decreased levels of cleaved caspase\u20103 and poly (ADP\u2010ribosyl) polymerase (PARP) and decreased terminal dUTP nick end labeling\u2010 (TUNEL\u2010) positive staining in alveolar epithelial cells and reduced ERK activation, which suggested reduced apoptosis <jats:italic>in vivo<\/jats:italic>. EGFR inhibition decreased hyperoxia (95%)\u2010induced apoptosis and ERK in murine alveolar epithelial cells <jats:italic>in vitro<\/jats:italic>, and CRISPR\u2010mediated EGFR deletion reduced hyperoxia\u2010induced apoptosis and ERK in human alveolar epithelial cells <jats:italic>in vitro<\/jats:italic>. <jats:italic>Innovation<\/jats:italic>. This work defines a protective role of EGFR inhibition to decrease apoptosis in lung injury induced by 100% oxygen. This further characterizes the complex role of EGFR in acute lung injury and outlines a novel hyperoxia\u2010induced cell death pathway that warrants further study. <jats:italic>Conclusion<\/jats:italic>. In conditions of severe hyperoxia (&gt;95% for &gt;24\u2009h), EGFR inhibition led to improved survival, decreased lung injury, and reduced cell death. These findings further elucidate the complex role of EGFR in acute lung injury.<\/jats:p>","DOI":"10.1155\/2022\/9518592","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T22:20:15Z","timestamp":1663712415000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Epidermal Growth Factor Receptor Inhibition Is Protective in Hyperoxia\u2010Induced Lung Injury"],"prefix":"10.1155","volume":"2022","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7350-7211","authenticated-orcid":false,"given":"Zachary 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