{"doi":"10.1093/toxsci/kfaa111","title":"Regulation of Lung Macrophage Activation and Oxidative Stress Following Ozone Exposure by Farnesoid X Receptor","abstract":"Inflammatory macrophages are known to contribute to ozone toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating bile acid and lipid homeostasis; it also exerts anti-inflammatory activity by suppressing macrophage NF-κB. Herein, we analyzed the role of FXR in regulating macrophage activation in the lung following ozone exposure. Treatment of wild-type (WT) mice with ozone (0.8 ppm, 3 h) resulted in increases in proinflammatory (F4/80+CD11c+CD11b+Ly6CHi) and anti-inflammatory (F4/80+CD11c+CD11b+Ly6CLo) macrophages in the lung. The accumulation of proinflammatory macrophages was increased in FXR-/- mice compared with WT mice; however, anti-inflammatory macrophage activation was blunted as reflected by reduced arginase and mannose receptor expression, a response correlated with decreased Nur77. This was associated with prolonged oxidative stress, as measured by 4-hydroxynonenal-modified proteins in the lung. Loss of FXR was accompanied by protracted increases in lung NF-κB activity and its target, inducible nitric oxide synthase in response to ozone. Levels of Tnf-α, Il-1β, Ccr2, Ccl2, Cx3cr1, and Cx3cl1 were also increased in lungs of FXR-/- relative to WT mice; conversely, genes regulating lipid homeostasis including Lxrα, Apoe, Vldlr, Abcg1, and Abca1 were downregulated, irrespective of ozone exposure. In FXR-/- mice, ozone caused an increase in total lung phospholipids, with no effect on SP-B or SP-D. Dyslipidemia was correlated with blunting of ozone-induced increases in positive end-expiratory pressure-dependent quasi-static pressure volume curves indicating a stiffer lung in FXR-/- mice. These findings identify FXR as a regulator of macrophage activation following ozone exposure suggesting that FXR ligands may be useful in mitigating inflammation and oxidative stress induced by pulmonary irritants.","journal":"Toxicological Sciences","year":2020,"id":100187,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":29,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9565,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":246449,"name":"Grace L. Guo","orcid":"0000-0002-2666-0635","position":1,"is_corresponding":false},{"id":305847,"name":"Bo Kong","orcid":"0000-0002-8200-7817","position":2,"is_corresponding":false},{"id":492157,"name":"Elena Abramova","orcid":"0000-0002-4249-8033","position":3,"is_corresponding":false},{"id":493103,"name":"Jessica A. Cervelli","orcid":null,"position":4,"is_corresponding":false},{"id":492158,"name":"Andrew J. Gow","orcid":"0000-0003-0876-5158","position":5,"is_corresponding":false},{"id":304789,"name":"Jeffrey D. Laskin","orcid":"0000-0003-1603-7388","position":6,"is_corresponding":false},{"id":304790,"name":"Debra L. Laskin","orcid":"0000-0003-1832-7311","position":7,"is_corresponding":false},{"id":493102,"name":"Mary Francis","orcid":null,"position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-18T22:38:35.493878Z","pmid":"32984886","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}