{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:43:01Z","timestamp":1787316181221,"version":"build-2736575974"},"reference-count":59,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":22,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001109","name":"Flinn Foundation","doi-asserted-by":"publisher","award":["23\u201012143"],"award-info":[{"award-number":["23\u201012143"]}],"id":[{"id":"10.13039\/100001109","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["physoc.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Physiological Reports"],"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Repeated low\u2010dose administration of lipopolysaccharide (LPS) attenuates subsequent fetal responses, which makes it challenging to investigate interventions to prolonged exposure. Our aim was to develop a fetal inflammatory response syndrome (FIRS) model that consistently and effectively elicits a marked physiological response to increasing LPS doses. Four intravenous LPS boluses (0.3, 1.5, 3, and 15\u2009\u03bcg) were administered to fetal sheep over 5\u2009days. Physiological responses were measured via blood gases, pH, lactate, and cortisol concentrations. Fetal peripheral blood mononuclear cells (PBMCs) were analyzed for transcriptomic changes and tissue cytokine expression postmortem. All LPS challenges increased lactate, cortisol, and pCO\n                    <jats:sub>2<\/jats:sub>\n                    concentrations and decreased pH and pO\n                    <jats:sub>2<\/jats:sub>\n                    levels at 3 and 5 hours. No interaction was found between day (increasing LPS doses) and hour (LPS response to each dose). PBMC numbers increase with LPS challenges. Transcriptional analysis on PBMCs identified several enriched gene clusters indicating upregulation of inflammatory gene signatures along with complement activation and NF\u03baB signaling pathways. Expression of pro\u2010inflammatory cytokines (TNF\u03b1, IL\u20106, or IL\u20101\u03b2) was measured in lung, heart, liver, placenta, and spleen. Physiological indices show both respiratory and metabolic acidosis with successive and increasing LPS challenges that demonstrate a robust systemic response despite tachyphylaxis to LPS in fetal sheep.\n                  <\/jats:p>","DOI":"10.14814\/phy2.70316","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T23:36:35Z","timestamp":1745451395000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Systemic inflammatory responses to repeated and increasing endotoxin challenges in fetal sheep"],"prefix":"10.14814","volume":"13","author":[{"given":"Sanya","family":"Kathuria","sequence":"first","affiliation":[{"name":"School of Animal and Comparative Biomedical Sciences University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akash","family":"Gupta","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayna R.","family":"Tracy","sequence":"additional","affiliation":[{"name":"School of Animal and Comparative Biomedical Sciences University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa I.","family":"Luna Ramirez","sequence":"additional","affiliation":[{"name":"School of Animal and Comparative Biomedical Sciences University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Senthil Kumar","family":"Thulasingam","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, College of Medicine University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nahla","family":"Zaghloul","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, College of Medicine University of Arizona  Tucson Arizona USA"},{"name":"Division of Neonatology, Department of Pediatrics, College of Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Division of Neonatology, Department of Pediatrics, College of Medicine University of Arizona  Tucson Arizona USA"},{"name":"Division of Neonatology, Department of Pediatrics, College of Medicine University of Florida  Gainesville Florida USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5851-0439","authenticated-orcid":false,"given":"Sean W.","family":"Limesand","sequence":"additional","affiliation":[{"name":"School of Animal and Comparative Biomedical Sciences University of Arizona  Tucson Arizona USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2023.1129413"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11250-020-02491-4"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2009.07.009"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.709309"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.00649"},{"key":"e_1_2_11_7_1","article-title":"Antibiotic regimens for management of intra\u2010amniotic infection","volume":"2014","author":"Chapman E.","year":"2014","journal-title":"Cochrane Database of Systematic Reviews"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2020.09.044"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00365.2019"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1530\/JOE-21-0071"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-020-01852-y"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2567.2009.03143.x"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-200212000-00021"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clp.2014.10.011"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1155\/S0962935193000687"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/1753425913488430"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.1994.tb01115.x"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13171"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1097\/GRF.0b013e31811ebef6"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/6614990"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010021\u201089542\u20104"},{"key":"e_1_2_11_22_1","first-page":"941","article-title":"The relationship of amniotic fluid cytokines and preterm delivery, amniotic fluid infection, histologic chorioamnionitis, and chorioamnion infection","volume":"81","author":"Hillier S. L.","year":"1993","journal-title":"Obstetrics and Gynecology"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-024-03092-9"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.3389\/fped.2022.796702"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2022.114049"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-021-01633-0"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.162.5.2003044"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2020.101146"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2019.05.030"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-0033-1361823"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1300270"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1210\/en.2018-00540"},{"issue":"476","key":"e_1_2_11_33_1","first-page":"e471","article-title":"Thymic changes after chorioamnionitis induced by intraamniotic lipopolysaccharide in fetal sheep","volume":"202","author":"Kunzmann S.","year":"2010","journal-title":"American Journal of Obstetrics and Gynecology"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0038257"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00110.2014"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1097\/AOG.0b013e3182073fbf"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/sigtrans.2017.23"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fmed.2023.1191254"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1210\/endocr\/bqad177"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpregu.00388.2012"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.165.6.2108053"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.siny.2020.101142"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1186\/1476-9255-9-1"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajog.2004.11.035"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkm226"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9378(89)90172-5"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-0528.2006.01120.x"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1502613"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac194"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0209510"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1016\/0046-8177(94)90195-3"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpendo.2000.278.5.E839"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1309\/RV6E9BMC9954A2WU"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-023-01988-x"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.earlhumdev.2016.06.001"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-020-00558-8"},{"key":"e_1_2_11_58_1","doi-asserted-by":"publisher","DOI":"10.1159\/000243921"},{"key":"e_1_2_11_59_1","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2010-3875"},{"key":"e_1_2_11_60_1","doi-asserted-by":"publisher","DOI":"10.1177\/1753425920928388"}],"container-title":["Physiological Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/pdf\/10.14814\/phy2.70316","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T05:40:27Z","timestamp":1745818827000},"score":1,"resource":{"primary":{"URL":"https:\/\/physoc.onlinelibrary.wiley.com\/doi\/10.14814\/phy2.70316"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4]]},"references-count":59,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.14814\/phy2.70316"],"URL":"https:\/\/doi.org\/10.14814\/phy2.70316","archive":["Portico"],"relation":{},"ISSN":["2051-817X","2051-817X"],"issn-type":[{"value":"2051-817X","type":"print"},{"value":"2051-817X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4]]},"assertion":[{"value":"2025-02-27","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-03-28","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-04-23","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70316"}}