{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:40:01Z","timestamp":1768470001158,"version":"3.49.0"},"reference-count":36,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,11,14]],"date-time":"2021-11-14T00:00:00Z","timestamp":1636848000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["P20 GM135000-01A1"],"award-info":[{"award-number":["P20 GM135000-01A1"]}]},{"name":"National Institute of Health","award":["P20 GM135002"],"award-info":[{"award-number":["P20 GM135002"]}]},{"DOI":"10.13039\/100012429","name":"Louisiana State University School of Veterinary Medicine","doi-asserted-by":"publisher","award":["VCS CORP grant"],"award-info":[{"award-number":["VCS CORP grant"]}],"id":[{"id":"10.13039\/100012429","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biology"],"abstract":"<jats:p>Preeclampsia (PE) is a multisystemic disease of pregnancy affecting 2\u20138% of women worldwide. PE-induced liver disease is a rare but important complication of pregnancy. The pathogenesis of liver dysfunction in PE is poorly understood, but is correlated with dysregulated angiogenic, inflammatory, and hypoxic events in the early phase of placental development. Because BPH\/5 mice develop the maternal and fetal hallmarks of PE during pregnancy, we hypothesized that they may also share the clinicopathologic findings of the human PE-associated hemolysis elevated liver transaminases low platelets (HELLP) syndrome. Using this model, we determined that microangiopathic hemolysis, thrombocytopenia, and elevated liver enzymes do not occur in mid to late gestation. Pregnant BPH\/5 mice do not develop histologic evidence of hepatic inflammation, but they do have increased microsteatosis scores at preconception and in mid to late gestation that progress to macrosteatosis in a subset of mice in late gestation. The transcriptional upregulation of TNF-\u03b1, CXCL-10, and TLR-2 occurs in mid gestation prior to the onset of macrosteatosis. The BPH\/5 female mouse is not a model of HELLP syndrome, but may be a model of fatty liver disease associated with pregnancy.<\/jats:p>","DOI":"10.3390\/biology10111179","type":"journal-article","created":{"date-parts":[[2021,11,14]],"date-time":"2021-11-14T20:48:36Z","timestamp":1636922916000},"page":"1179","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The BPH\/5 Mouse Model of Superimposed Preeclampsia Is Not a Model of HELLP Syndrome"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1082-1155","authenticated-orcid":false,"given":"Andrea N.","family":"Johnston","sequence":"first","affiliation":[{"name":"Departments of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tifini L.","family":"Batts","sequence":"additional","affiliation":[{"name":"Departments of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7366-4391","authenticated-orcid":false,"given":"Ingeborg M.","family":"Langohr","sequence":"additional","affiliation":[{"name":"Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cambri","family":"Moeller","sequence":"additional","affiliation":[{"name":"Departments of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0723-8313","authenticated-orcid":false,"given":"Chin-Chi","family":"Liu","sequence":"additional","affiliation":[{"name":"Departments of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jennifer L.","family":"Sones","sequence":"additional","affiliation":[{"name":"Departments of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1053\/j.semperi.2011.09.011","article-title":"Maternal Mortality from Preeclampsia\/Eclampsia","volume":"36","author":"Ghulmiyyah","year":"2012","journal-title":"Semin. Perinatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/B978-0-12-385855-9.00004-7","article-title":"Biochemistry of Hellp Syndrome","volume":"53","author":"Benedetto","year":"2011","journal-title":"Adv. Clin. Chem."},{"key":"ref_3","first-page":"1","article-title":"Preeclampsia and Hellp Syndrome, the Role of the Liver","volume":"34","author":"Alese","year":"2019","journal-title":"J. Matern. Fetal. Neonatal Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1080\/jmf.16.5.287.293","article-title":"A Clinicohistopathologic Comparison between Hellp Syndrome and Severe Preeclampsia","volume":"16","author":"Smulian","year":"2004","journal-title":"J. Matern. Fetal. Neonatal Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1007\/s004040050238","article-title":"Plasma Endothelin and Big Endothelin Levels in Women with Severe Preeclampsia or Hellp-Syndrome","volume":"262","author":"Bussen","year":"1999","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1111\/j.1538-7836.2006.02205.x","article-title":"Acute Activation of the Endothelium Results in Increased Levels of Active Von Willebrand Factor in Hemolysis, Elevated Liver Enzymes and Low Platelets (Hellp) Syndrome","volume":"4","author":"Hulstein","year":"2006","journal-title":"J. Thromb. Haemost."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.cyto.2007.08.010","article-title":"Inflammatory Cytokines Patterns in the Placenta of Pregnancies Complicated by Hellp (Hemolysis, Elevated Liver Enzyme, and Low Platelet) Syndrome","volume":"40","author":"Tranquilli","year":"2007","journal-title":"Cytokine"},{"key":"ref_8","unstructured":"Khalid, F., and Tonismae, T. (2020). Hellp Syndrome. Statpearls, StatPearls Publishing."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"816","DOI":"10.2174\/1389201019666180712115215","article-title":"Hellp Syndrome: Pathophysiology and Current Therapies","volume":"19","author":"Wallace","year":"2018","journal-title":"Curr. Pharm. Biotechnol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1016\/j.placenta.2014.07.009","article-title":"Trophoblast Debris Extruded from Preeclamptic Placentae Activates Endothelial Cells: A Mechanism by Which the Placenta Communicates with the Maternal Endothelium","volume":"35","author":"Shen","year":"2014","journal-title":"Placenta"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Haram, K., Svendsen, E., and Abildgaard, U. (2009). The Hellp Syndrome: Clinical Issues and Management. A Review. BMC Pregnancy Childbirth, 9.","DOI":"10.1186\/1471-2393-9-8"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1161\/hy02t2.102904","article-title":"Discovery of a Spontaneous Genetic Mouse Model of Preeclampsia","volume":"39","author":"Davisson","year":"2002","journal-title":"Hypertension"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.jri.2017.04.002","article-title":"The Decidua of Preeclamptic-Like Bph\/5 Mice Exhibits an Exaggerated Inflammatory Response During Early Pregnancy","volume":"120","author":"Heyward","year":"2017","journal-title":"J. Reprod. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/j.mod.2014.04.001","article-title":"Novel Expression of Egfl7 in Placental Trophoblast and Endothelial Cells and Its Implication in Preeclampsia","volume":"133","author":"Lacko","year":"2014","journal-title":"Mech. Dev."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Olson, K.N., Reijnders, D., Gomes, V.C.L., Hebert, R.C., Liu, C.C., Stephens, J.M., Redman, L.M., Douglas, N.C., and Sones, J.L. (2020). Complement in Reproductive White Adipose Tissue Characterizes the Obese Preeclamptic-Like Bph\/5 Mouse Prior to and During Pregnancy. Biology, 9.","DOI":"10.3390\/biology9090304"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1152\/physiolgenomics.00115.2017","article-title":"Celecoxib Restores Angiogenic Factor Expression at the Maternal-Fetal Interface in the Bph\/5 Mouse Model of Preeclampsia","volume":"50","author":"Reijnders","year":"2018","journal-title":"Physiol. Genom."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e75351","DOI":"10.1172\/jci.insight.75351","article-title":"Decidual Cox2 Inhibition Improves Fetal and Maternal Outcomes in a Preeclampsia-Like Mouse Model","volume":"1","author":"Sones","year":"2016","journal-title":"JCI Insight"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2574","DOI":"10.1096\/fj.201701008R","article-title":"Angiogenic Factor Imbalance Precedes Complement Deposition in Placentae of the Bph\/5 Model of Preeclampsia","volume":"32","author":"Sones","year":"2018","journal-title":"FASEB J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1161\/HYPERTENSIONAHA.107.107219","article-title":"Chronic Tempol Prevents Hypertension, Proteinuria, and Poor Feto-Placental Outcomes in Bph\/5 Mouse Model of Preeclampsia","volume":"51","author":"Hoffmann","year":"2008","journal-title":"Hypertension"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1161\/HYPERTENSIONAHA.110.160242","article-title":"Adenoviral Delivery of Vegf121 Early in Pregnancy Prevents Spontaneous Development of Preeclampsia in Bph\/5 Mice","volume":"57","author":"Woods","year":"2011","journal-title":"Hypertension"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R49","DOI":"10.1152\/ajpregu.00334.2018","article-title":"Dyslipidemia and the Role of Adipose Tissue in Early Pregnancy in the Bph\/5 Mouse Model for Preeclampsia","volume":"317","author":"Reijnders","year":"2019","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"R485","DOI":"10.1152\/ajpregu.00512.2016","article-title":"Adverse Metabolic Phenotype of Female Offspring Exposed to Preeclampsia in Utero: A Characterization of the Bph\/5 Mouse in Postnatal Life","volume":"312","author":"Sutton","year":"2017","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1095\/biolreprod.106.053603","article-title":"Severe Feto-Placental Abnormalities Precede the Onset of Hypertension and Proteinuria in a Mouse Model of Preeclampsia","volume":"75","author":"Dokras","year":"2006","journal-title":"Biol. Reprod."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Liang, W., Menke, A.L., Driessen, A., Koek, G.H., Lindeman, J.H., Stoop, R., Havekes, L.M., Kleemann, R., and van den Hoek, A.M. (2014). Establishment of a General Nafld Scoring System for Rodent Models and Comparison to Human Liver Pathology. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0115922"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3960","DOI":"10.1172\/JCI64583","article-title":"Er Stress in the Brain Subfornical Organ Mediates Angiotensin-Dependent Hypertension","volume":"122","author":"Young","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of Relative Gene Expression Data Using Real-Time Quantitative Pcr and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41598-017-18260-7","article-title":"Hepatic dysfunction and thrombocytopenia induced by excess sFlt1 in mice lacking endothelial nitric oxide synthase","volume":"8","author":"Oe","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/S1071-5576(03)00009-1","article-title":"Evaluation of a rat model of preeclampsia for HELLP syndrome characteristics","volume":"10","author":"Isler","year":"2003","journal-title":"J. Soc. Gynecol. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Di Lorenzo, A., Bolli, E., Tarone, L., Cavallo, F., and Conti, L. (2020). Toll-Like Receptor 2 at the Crossroad between Cancer Cells, the Immune System, and the Microbiota. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21249418"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.autrev.2013.10.010","article-title":"Chemokine (C-X-C Motif) Ligand (Cxcl)10 in Autoimmune Diseases","volume":"13","author":"Antonelli","year":"2014","journal-title":"Autoimmun. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/0002-9378(90)90376-I","article-title":"The Hellp Syndrome (Hemolysis, Elevated Liver Enzymes, and Low Platelets): Much Ado About Nothing?","volume":"162","author":"Sibai","year":"1990","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/0020-7292(91)90762-T","article-title":"Hellp Syndrome--a Syndrome of Hemolysis, Elevated Liver Enzymes and Low Platelet Count--Complicating Preeclampsia-Eclampsia","volume":"36","author":"Reubinoff","year":"1991","journal-title":"Int. J. Gynaecol. Obstet."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1295","DOI":"10.1161\/HYPERTENSIONAHA.107.104844","article-title":"Severe Preeclampsia with and without Hellp Differ with Regard to Placental Pathology","volume":"51","author":"Vinnars","year":"2008","journal-title":"Hypertension"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.preghy.2017.02.004","article-title":"Dysregulation of the Fas\/Fasl System in an Experimental Animal Model of Hellp Syndrome","volume":"8","author":"Gibbens","year":"2017","journal-title":"Pregnancy Hypertens."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"R195","DOI":"10.1152\/ajpregu.00272.2019","article-title":"Fas Ligand Neutralization Attenuates Hypertension, Endothelin-1, and Placental Inflammation in an Animal Model of Hellp Syndrome","volume":"319","author":"Gibbens","year":"2020","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.ejogrb.2019.10.021","article-title":"Angiogenic Profiling in Hellp Syndrome Cases with or without Hypertension and Proteinuria","volume":"243","author":"Trottmann","year":"2019","journal-title":"Eur. J. Obstet. Gynecol. Reprod. Biol."}],"container-title":["Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-7737\/10\/11\/1179\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:30:03Z","timestamp":1760167803000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-7737\/10\/11\/1179"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,14]]},"references-count":36,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["biology10111179"],"URL":"https:\/\/doi.org\/10.3390\/biology10111179","relation":{},"ISSN":["2079-7737"],"issn-type":[{"value":"2079-7737","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,14]]}}}