{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T01:23:41Z","timestamp":1760059421901,"version":"build-2065373602"},"reference-count":41,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T00:00:00Z","timestamp":1749600000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Health and Medical Research Council of Australia","award":["1164954","1105526","1175843"],"award-info":[{"award-number":["1164954","1105526","1175843"]}]},{"name":"Cerebral Palsy Alliance","award":["1164954","1105526","1175843"],"award-info":[{"award-number":["1164954","1105526","1175843"]}]},{"name":"Victorian Government\u2019s Operational Infrastructure Support Program","award":["1164954","1105526","1175843"],"award-info":[{"award-number":["1164954","1105526","1175843"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Antenatal inflammation\/infection is a major cause of neonatal apnoea and hypoventilation. Prostaglandin E2 (PGE2) is a key inflammatory mediator associated with depression of fetal and neonatal breathing. We aimed to determine whether antenatal ibuprofen, a cyclooxygenase inhibitor that reduces synthesis of PGE2, restores fetal breathing movements (FBM) in late-gestation fetal sheep exposed to systemic lipopolysaccharide (LPS). Fetal sheep (125 days gestation, d; term ~148 d) were instrumentally monitored for continuous measurement of FBM and physiological parameters. At 130 d fetuses were randomly allocated between groups receiving i.v. saline (CTLSAL, n = 9), escalating doses of LPS (i.v.) over 3 days (LPSSAL, n = 8), or ibuprofen one hour after each LPS dose (LPSIBU, n = 8). Regular plasma samples were collected for PGE2 assessment. At 135 d, cerebrospinal fluid and brainstem tissue were collected at autopsy for assessments of PGE2 expression, and immunohistochemical quantification of astrocytes and microglia within key brainstem respiratory centres was performed to assess inflammation. LPS exposure increased PGE2 levels in plasma, cerebrospinal fluid and the RTN\/pFRG (p &lt; 0.05) and decreased the incidence, amplitude and amount of the accentuated (&gt;5 mmHg) FBMs. Ibuprofen reduced plasma and RTN\/pFRG PGE2 expression (p &lt; 0.01 and p = 0.031, respectively) but did not restore FBMs. Astrocyte and microglial density increased in the RTN\/pFRG, NTS and raphe nucleus in LPSIBU fetuses, compared to LPSSAL (p &lt; 0.05). Antenatal ibuprofen treatment did not restore depressed FBM, despite reducing the circulating and brainstem PGE2 levels in LPS-exposed fetal sheep. Other inflammatory pathways or more specific targeting of PGE2 may be more effective in preventing apnoea caused by exposure to intrauterine infection\/inflammation.<\/jats:p>","DOI":"10.3390\/ijms26125591","type":"journal-article","created":{"date-parts":[[2025,6,11]],"date-time":"2025-06-11T08:18:06Z","timestamp":1749629886000},"page":"5591","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Ibuprofen Does Not Prevent Inhibition of Fetal Breathing Movements Caused by Intrauterine Inflammation in Fetal Sheep"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0396-9760","authenticated-orcid":false,"given":"Nhi T.","family":"Tran","sequence":"first","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"},{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Vanesa","family":"Stojanovska","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"},{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sharmony B.","family":"Kelly","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"},{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0840-6144","authenticated-orcid":false,"given":"Kayla","family":"Vidinopoulos","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"},{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John","family":"Atta","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"},{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eva","family":"Matthews-Staindl","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Valerie A.","family":"Zahra","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"},{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen","family":"Pham","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"},{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6859-0620","authenticated-orcid":false,"given":"Eric A. P.","family":"Herlenius","sequence":"additional","affiliation":[{"name":"Department of Women\u2019s and Children\u2019s Health, Karolinska Institutet, 17176 Solna, Sweden"},{"name":"Astrid Lindgren Children\u2019s Hospital, Karolinska University Hospital Stockholm, 17176 Solna, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart B.","family":"Hooper","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"},{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1060-513X","authenticated-orcid":false,"given":"Beth J.","family":"Allison","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"},{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6374-9372","authenticated-orcid":false,"given":"Robert","family":"Galinsky","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"},{"name":"Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Graeme R.","family":"Polglase","sequence":"additional","affiliation":[{"name":"The Ritchie Centre, Hudson Institute of Medical Research, Clayton, VIC 3168, Australia"},{"name":"Department of Pediatrics, Monash University, Clayton, VIC 3168, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.clp.2010.02.003","article-title":"Diagnosis and Management of Clinical Chorioamnionitis","volume":"37","author":"Tita","year":"2010","journal-title":"Clin. Perinatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1152\/japplphysiol.00995.2011","article-title":"Inflammation in utero exacerbates ventilation-induced brain injury in preterm lambs","volume":"112","author":"Polglase","year":"2012","journal-title":"J. Appl. Physiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1207","DOI":"10.1016\/j.jpeds.2015.08.053","article-title":"Prostaglandin E2 Mediates Cardiorespiratory Disturbances During Infection in Neonates","volume":"167","author":"Siljehav","year":"2015","journal-title":"J. Pediatr."},{"key":"ref_4","unstructured":"Chow, S.S.W., Creighton, P., Chambers, G.M., and Lui, K. (2022). Report of the Australian and New Zealand Neonatal Network 2020, ANZNN."},{"key":"ref_5","first-page":"Cd003481","article-title":"Ibuprofen for the treatment of patent ductus arteriosus in preterm or low birth weight (or both) infants","volume":"2","author":"Ohlsson","year":"2020","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1152\/jappl.1988.64.5.2160","article-title":"Prostaglandin E2 causes hypoventilation and apnea in newborn lambs","volume":"64","author":"Guerra","year":"1988","journal-title":"J. Appl. Physiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1113\/jphysiol.1984.sp015003","article-title":"The central control of fetal breathing and skeletal muscle movements","volume":"346","author":"Dawes","year":"1984","journal-title":"J. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1016\/0006-8993(94)90313-1","article-title":"Ontogenesis of prostaglandin E2 binding sites in the brainstem of the sheep","volume":"652","author":"Tai","year":"1994","journal-title":"Brain Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1111\/j.1440-1681.1998.tb02157.x","article-title":"Effects of prostaglandin E2 on renal function and lung liquid dynamics in foetal sheep","volume":"25","author":"Wlodek","year":"1998","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1016\/0002-9378(84)90681-1","article-title":"Meclofenamate and prostaglandin E2 affect breathing movements independently of glucose concentrations in fetal sheep","volume":"150","author":"Murai","year":"1984","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1152\/jappl.1995.78.4.1477","article-title":"Prostaglandin E2 decreases fetal breathing movements, but not pulmonary blood flow, in fetal sheep","volume":"78","author":"Savich","year":"1995","journal-title":"J. Appl. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9894","DOI":"10.1073\/pnas.0611468104","article-title":"The induced prostaglandin E2 pathway is a key regulator of the respiratory response to infection and hypoxia in neonates","volume":"104","author":"Hofstetter","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Stojanovska, V., Atta, J., Kelly, S.B., Zahra, V.A., Matthews-Staindl, E., Nitsos, I., Moxham, A., Pham, Y., Hooper, S.B., and Herlenius, E. (2022). Increased Prostaglandin E2 in Brainstem Respiratory Centers Is Associated with Inhibition of Breathing Movements in Fetal Sheep Exposed to Progressive Systemic Inflammation. Front. Physiol., 13.","DOI":"10.3389\/fphys.2022.841229"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1055\/s-2007-994156","article-title":"Fetal breathing movements within 24 hours of delivery in prematurity are related to histologic and clinical evidence of amnionitis","volume":"14","author":"Sherer","year":"1997","journal-title":"Am. J. Perinatol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1097\/00006250-198606000-00013","article-title":"Fetal breathing as a predictor of infection in premature rupture of the membranes","volume":"67","author":"Vintzileos","year":"1986","journal-title":"Obs. Gynecol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"280","DOI":"10.1136\/archdischild-2022-324695","article-title":"Effect of clinical chorioamnionitis on breathing effort in premature infants at birth: A retrospective case-control study","volume":"108","author":"Panneflek","year":"2023","journal-title":"Arch. Dis. Child. Fetal Neonatal Ed."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2539","DOI":"10.1007\/s00431-024-05508-4","article-title":"The influence of chorioamnionitis on respiratory drive and spontaneous breathing of premature infants at birth: A narrative review","volume":"183","author":"Panneflek","year":"2024","journal-title":"Eur. J. Pediatr."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"155","DOI":"10.5001\/omj.2010.49","article-title":"An overview of clinical pharmacology of Ibuprofen","volume":"25","author":"Bushra","year":"2010","journal-title":"Oman Med. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1007\/s11095-006-9905-5","article-title":"Brain uptake of nonsteroidal anti-inflammatory drugs: Ibuprofen, flurbiprofen, and indomethacin","volume":"23","author":"Parepally","year":"2006","journal-title":"Pharm. Res."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Wixey, J.A., Sukumar, K.R., Pretorius, R., Lee, K.M., Colditz, P.B., Bjorkman, S.T., and Chand, K.K. (2019). Ibuprofen Treatment Reduces the Neuroinflammatory Response and Associated Neuronal and White Matter Impairment in the Growth Restricted Newborn. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00541"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1007\/s12035-021-02654-w","article-title":"Neurovascular Unit Alterations in the Growth-Restricted Newborn Are Improved Following Ibuprofen Treatment","volume":"59","author":"Chand","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0006-8993(02)03006-8","article-title":"Behavioural and histopathological analyses of ibuprofen treatment on the effect of aggregated Abeta(1\u201342) injections in the rat","volume":"954","author":"Richardson","year":"2002","journal-title":"Brain Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2516","DOI":"10.1007\/s11064-020-03109-9","article-title":"Ibuprofen Exerts Antiepileptic and Neuroprotective Effects in the Rat Model of Pentylenetetrazol-Induced Epilepsy via the COX-2\/NLRP3\/IL-18 Pathway","volume":"45","author":"Liu","year":"2020","journal-title":"Neurochem. Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1186\/s12974-021-02238-4","article-title":"Interleukin-1 blockade attenuates white matter inflammation and oligodendrocyte loss after progressive systemic lipopolysaccharide exposure in near-term fetal sheep","volume":"18","author":"Kelly","year":"2021","journal-title":"J. Neuroinflammation"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1186\/s12974-023-02805-x","article-title":"Progressive inflammation reduces high-frequency EEG activity and cortical dendritic arborisation in late gestation fetal sheep","volume":"20","author":"Kelly","year":"2023","journal-title":"J. Neuroinflammation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.resp.2004.11.002","article-title":"Interleukin-1beta depresses hypoxic gasping and autoresuscitation in neonatal DBA\/1lacJ mice","volume":"146","author":"Hofstetter","year":"2005","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.resp.2013.04.022","article-title":"Lung inflammation induces IL-1\u03b2 expression in hypoglossal neurons in rat brainstem","volume":"188","author":"Jafri","year":"2013","journal-title":"Respir. Physiol. Neurobiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"326","DOI":"10.1203\/01.PDR.0000076665.62641.A2","article-title":"IL-1\u03b2 Depresses Respiration and Anoxic Survival via a Prostaglandin-Dependent Pathway in Neonatal Rats","volume":"54","author":"Olsson","year":"2003","journal-title":"Pediatr. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"987.984","DOI":"10.1096\/fasebj.30.1_supplement.987.4","article-title":"Disturbances in central respiratory rhythm generation may contribute to breathing disturbances in prematurely born mice","volume":"30","author":"Ramirez","year":"2016","journal-title":"FASEB J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1152\/japplphysiol.00542.2014","article-title":"Il-1beta and prostaglandin E2 attenuate the hypercapnic as well as the hypoxic respiratory response via prostaglandin E receptor type 3 in neonatal mice","volume":"117","author":"Siljehav","year":"2014","journal-title":"J. Appl. Physiol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"466","DOI":"10.1111\/j.1651-2227.2011.02564.x","article-title":"Intrapulmonary lipopolysaccharide exposure upregulates cytokine expression in the neonatal brainstem","volume":"101","author":"Balan","year":"2012","journal-title":"Acta Paediatr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1016\/j.yfrne.2011.12.002","article-title":"Cytokines and brain excitability","volume":"33","author":"Galic","year":"2012","journal-title":"Front. Neuroendocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1016\/0002-9378(88)90147-0","article-title":"The role of carbon dioxide in the generation of human fetal breathing movements","volume":"158","author":"Connors","year":"1988","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e14170","DOI":"10.7554\/eLife.14170","article-title":"CO2-evoked release of PGE2 modulates sighs and inspiration as demonstrated in brainstem organotypic culture","volume":"5","author":"Forsberg","year":"2016","journal-title":"eLife"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1113\/jphysiol.2014.279794","article-title":"Prostaglandin E2 differentially modulates the central control of eupnoea, sighs and gasping in mice","volume":"593","author":"Koch","year":"2015","journal-title":"J. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Stojanovska, V., Miller, S.L., Hooper, S.B., and Polglase, G.R. (2018). The Consequences of Preterm Birth and Chorioamnionitis on Brainstem Respiratory Centers: Implications for Neurochemical Development and Altered Functions by Inflammation and Prostaglandins. Front. Cell Neurosci., 12.","DOI":"10.3389\/fncel.2018.00026"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1863","DOI":"10.2174\/092986708785132915","article-title":"Therapeutic targets in prostaglandin E2 signaling for neurologic disease","volume":"15","author":"Cimino","year":"2008","journal-title":"Curr. Med. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1203\/01.PDR.0000145254.66447.C0","article-title":"Influence of Fetal Breathing Movements on Pulmonary Hemodynamics in Fetal Sheep","volume":"56","author":"Polglase","year":"2004","journal-title":"Pediatr. Res."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Badurdeen, S., Gill, A.W., Kluckow, M., Roberts, C.T., Galinsky, R., Klink, S., Miller, S.L., Davis, P.G., Schm\u00f6lzer, G.M., and Hooper, S.B. (2020). Excess cerebral oxygen delivery follows return of spontaneous circulation in near-term asphyxiated lambs. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-73453-x"},{"key":"ref_40","unstructured":"Johnson, J.K., Sudheimer, K.D., Davis, K.K., Kerndt, G.M., and Winn, B.M. (2021, August 31). The Sheep Brain Atlas. Available online: https:\/\/brains.anatomy.msu.edu\/brains\/sheep\/index.html."},{"key":"ref_41","unstructured":"Paxinos, G. (1986). The Rat Brain in Stereotaxic Coordinates, Academic Press. [2nd ed.]."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5591\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:50:04Z","timestamp":1760032204000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/12\/5591"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,11]]},"references-count":41,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["ijms26125591"],"URL":"https:\/\/doi.org\/10.3390\/ijms26125591","relation":{},"ISSN":["1422-0067"],"issn-type":[{"type":"electronic","value":"1422-0067"}],"subject":[],"published":{"date-parts":[[2025,6,11]]}}}