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We evaluated the contribution of eNAMPT (extracellular nicotinamide phosphoribosyltransferase), a damage-associated molecular pattern (DAMP) protein and TLR4 (Toll-like receptor 4) ligand, to the severity of whole-thorax lung irradiation (WTLI)-induced RILF. Wild-type (WT) and Nampt \u00a0+\/\u2212 heterozygous C57BL6 mice and nonhuman primates (NHPs, Macaca mulatta) were exposed to a single WTLI dose (9.8 or 10.7 Gy for NHPs, 20 Gy for mice). WT mice received IgG1 (control) or an eNAMPT-neutralizing polyclonal or monoclonal antibody (mAb) intraperitoneally 4 hours after WTLI and weekly thereafter. At 8\u201312 weeks after WTLI, NAMPT expression was assessed by immunohistochemistry, biochemistry, and plasma biomarker studies. RILF severity was determined by BAL protein\/cells, hematoxylin and eosin, and trichrome blue staining and soluble collagen assays. RNA sequencing and bioinformatic analyses identified differentially expressed lung tissue genes\/pathways. NAMPT lung tissue expression was increased in both WTLI-exposed WT mice and NHPs. Nampt \u00a0+\/\u2212 mice and eNAMPT polyclonal antibody\/mAb-treated mice exhibited significantly attenuated WTLI-mediated lung fibrosis with reduced: 1) NAMPT and trichrome blue staining; 2) dysregulated lung tissue expression of smooth muscle actin, p-SMAD2\/p-SMAD1\/5\/9, TGF-\u03b2, TSP1 (thrombospondin-1), NOX4, IL-1\u03b2, and NRF2; 3) plasma eNAMPT and IL-1\u03b2 concentrations; and 4) soluble collagen. Multiple WTLI-induced dysregulated differentially expressed lung tissue genes\/pathways with known tissue fibrosis involvement were each rectified in mice receiving eNAMPT mAbs.The eNAMPT\/TLR4 inflammatory network is essentially involved in radiation pathobiology, with eNAMPT neutralization an effective therapeutic strategy to reduce RILF severity.<\/jats:p>","DOI":"10.1165\/rcmb.2021-0357oc","type":"journal-article","created":{"date-parts":[[2022,2,15]],"date-time":"2022-02-15T16:47:12Z","timestamp":1644943632000},"page":"497-509","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":39,"title":["eNAMPT Is a Novel Damage-associated Molecular Pattern Protein That Contributes to the Severity of Radiation-Induced Lung Fibrosis"],"prefix":"10.1093","volume":"66","author":[{"given":"Alexander N.","family":"Garcia","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6363-2414","authenticated-orcid":false,"given":"Nancy G.","family":"Casanova","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carrie L.","family":"Kempf","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadeo","family":"Bermudez","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4450-4510","authenticated-orcid":false,"given":"Daniel G.","family":"Valera","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0123-2909","authenticated-orcid":false,"given":"Jin H.","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4226-8294","authenticated-orcid":false,"given":"Xiaoguang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Cai","sequence":"additional","affiliation":[{"name":"Department of Anesthesiology, University of California Los Angeles, Los Angeles, California"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liliana","family":"Moreno-Vinasco","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taylor","family":"Gregory","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radu C.","family":"Oita","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vivian Reyes","family":"Hernon","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5521-9841","authenticated-orcid":false,"given":"Sara M.","family":"Camp","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Rogers","sequence":"additional","affiliation":[{"name":"ChromoLogic LLC, Monrovia, California; 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