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In rodents, acute O3-induced inflammation and injury can be mitigated by pre-exposure to relatively low concentrations of O3, a phenomenon referred to as tolerance. Although tolerance was first described long ago, the underlying mechanisms are not known. We hypothesized that alveolar macrophages (AMs) play a key role in tolerance to O3 based on prior studies with other exposures. To enable our studies, we first generated a mouse model in which female C57BL6\/NJ mice were pre-exposed to filtered air or 0.8\u2009ppm O3 for 4 days (4\u2009h\/day), then challenged with 2\u2009ppm O3 (3\u2009h) 2\u2009days later, and phenotyped for airway inflammation and injury 6 or 24\u2009h thereafter. As expected, pre-exposure to O3 resulted in significantly reduced airway inflammation and injury 24\u2009h following O3 challenge. Tolerance was associated with regenerative hyperplasia in the terminal bronchioles and changes in the frequency of proliferating alveolar type 2 cells. O3 pre-exposure altered the expression of \u223c1,500 genes in AMs, most notably downregulation of Toll-like receptor and proinflammatory cytokine signaling pathways, suggesting AMs had become hypo-responsive. Depletion of tolerized AMs prior to acute O3 challenge did not, however, alter inflammation and injury. Additionally, adoptive transfer of tolerized AM to na\u00efve recipient mice failed to alter responses to acute O3 challenge. In total, our results argue against an important role for AMs in tolerance to ozone and suggest that other cell types are involved.<\/jats:p>","DOI":"10.1093\/toxsci\/kfaf095","type":"journal-article","created":{"date-parts":[[2025,7,25]],"date-time":"2025-07-25T17:12:26Z","timestamp":1753463546000},"page":"487-497","source":"Crossref","is-referenced-by-count":4,"title":["Evaluating the role of alveolar macrophages in tolerance to ozone"],"prefix":"10.1093","volume":"207","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5305-0445","authenticated-orcid":false,"given":"Gregory J","family":"Smith","sequence":"first","affiliation":[{"name":"Department of Genetics, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Morgan","family":"Nalesnik","sequence":"additional","affiliation":[{"name":"Curriculum in Toxicology and Environmental Medicine, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1998-1307","authenticated-orcid":false,"given":"Robert M","family":"Immormino","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of North Carolina School of Medicine , Chapel Hill, NC 27599,","place":["United States"]},{"name":"Center for Environmental Medicine, Asthma and Lung Biology, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremy M","family":"Simon","sequence":"additional","affiliation":[{"name":"Department of Genetics, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599,","place":["United States"]},{"name":"Neuroscience Center, University of North Carolina School of Medicine , Chapel Hill, NC 27599,","place":["United States"]},{"name":"Department of Data Science, Dana-Farber Cancer Institute , Boston, MA 02115,","place":["United States"]},{"name":"Department of Biostatistics, Harvard T. 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Chan School of Public Health , Boston, MA 02115,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jack R","family":"Harkema","sequence":"additional","affiliation":[{"name":"Department of Pathobiology and Diagnostic Investigation, Michigan State University , East Lansing, MI 48824,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason R","family":"Mock","sequence":"additional","affiliation":[{"name":"Division of Pulmonary Diseases and Critical Care Medicine, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599,","place":["United States"]},{"name":"Marsico Lung Institute, University of North Carolina at Chapel Hill , Chapel Hill, NC 27599,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy P","family":"Moran","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of North Carolina School of Medicine , Chapel 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