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We previously demonstrated that leukemia inhibitory factor (LIF), an IL-6 family cytokine, is produced by type II alveolar epithelial cells (ATII) and is critical for tissue protection during bacterial pneumonia. However, the target cells and mechanisms of LIF-mediated protection remain unknown. Here, we demonstrate that antibody-induced LIF blockade remodels the lung epithelial transcriptome in association with increased apoptosis. Based on these data, we performed pneumonia studies using a novel mouse model in which LIFR (the unique receptor for LIF) is absent in lung epithelium. Although LIFR is expressed on the surface of epithelial cells, its absence only minimally contributed to tissue protection during pneumonia. Single-cell RNA-sequencing (scRNAseq) was conducted to identify adult murine lung cell types most prominently expressing Lifr, revealing endothelial cells, mesenchymal cells, and ATIIs as major sources of Lifr. Sequencing data indicated that ATII cells were significantly impacted by pneumonia, with additional differences observed in response to LIF neutralization, including but not limited to gene programs related to cell death, injury, and inflammation. Overall, our data suggest that LIF signaling on epithelial cells alters responses in this cell type during pneumonia. However, our results also suggest separate and perhaps more prominent roles of LIFR in other cell types, such as endothelial cells or mesenchymal cells, which provide grounds for future investigation.<\/jats:p>","DOI":"10.1152\/ajplung.00325.2021","type":"journal-article","created":{"date-parts":[[2022,2,9]],"date-time":"2022-02-09T08:00:52Z","timestamp":1644393652000},"page":"L550-L563","update-policy":"https:\/\/doi.org\/10.1152\/aps-crossmark-policy","source":"Crossref","is-referenced-by-count":13,"title":["Epithelial LIF signaling limits apoptosis and lung injury during bacterial pneumonia"],"prefix":"10.1152","volume":"322","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5820-4514","authenticated-orcid":true,"given":"Elim","family":"Na","sequence":"first","affiliation":[{"name":"Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts"},{"name":"Department of Medicine, Boston University School of Medicine, Boston, 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