{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,22]],"date-time":"2026-01-22T05:45:45Z","timestamp":1769060745205,"version":"3.49.0"},"reference-count":42,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T00:00:00Z","timestamp":1634688000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["18H02649, 20K21516, 21H02722"],"award-info":[{"award-number":["18H02649, 20K21516, 21H02722"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Visceral leishmaniasis (VL) is the most severe form of leishmaniasis caused by protozoan parasites of the genus Leishmania. Hepatomegaly is one of the most frequent clinical manifestations of VL, whereas immunopathology of the symptom has not been well investigated. Using our chronic model of experimental VL, we examined the influence of Leishmania donovani infection on the liver by clinical, histological, and biochemical analyses. The infected mice showed increased liver weight 24 weeks post-infection. Although an increase in serum ALT and inflammatory cell accumulation were observed in the livers of infected mice, no apparent parenchymal necrosis or fibrosis was observed. Tissue water content analyses demonstrated that increased liver weight was predominantly due to an increase in water weight. Together with the finding of hepatic sinusoidal dilation, these results suggested that edema associated with sinusoidal dilation causes hepatomegaly in L. donovani infection. Immunostaining of platelets and erythrocytes showed no thrombus formation or damage to the sinusoidal endothelium in the liver of infected mice. Taken together, these results suggest that hepatomegaly during experimental VL is caused by non-obstructive sinusoidal dilation.<\/jats:p>","DOI":"10.3390\/pathogens10111356","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T21:31:26Z","timestamp":1634765486000},"page":"1356","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Hepatomegaly Associated with Non-Obstructive Sinusoidal Dilation in Experimental Visceral Leishmaniasis"],"prefix":"10.3390","volume":"10","author":[{"given":"Kota","family":"Maeda","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sonya","family":"Sadoughi","sequence":"additional","affiliation":[{"name":"Department of Veterinary Medicine, University of Cambridge, Cambridge CB3 0ES, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ayako","family":"Morimoto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kazuyuki","family":"Uchida","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology, Department of Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James","family":"Chambers","sequence":"additional","affiliation":[{"name":"Laboratory of Veterinary Pathology, Department of Veterinary Medical Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chizu","family":"Sanjoba","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Junya","family":"Yamagishi","sequence":"additional","affiliation":[{"name":"Division of Collaboration and Education, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan"},{"name":"International Collaboration Unit, International Institute for Zoonosis Control, Hokkaido University, Sapporo 001-0020, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuyuki","family":"Goto","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Department of Animal Resource Sciences, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Tokyo 113-8657, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,10,20]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (2021). Leishmaniasis, World Health Organization."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Sarkari, B., Naraki, T., Ghatee, M.A., Khabisi, S.A., and Davami, M.H. (2016). Visceral Leishmaniasis in Southwestern Iran: A Retrospective Clinico-Hematological Analysis of 380 Consecutive Hospitalized Cases (1999\u20132014). PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150406"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"485","DOI":"10.12669\/pjms.292.3151","article-title":"Visceral leishmaniasis: Clinical and demographic features in an African population","volume":"29","author":"Nail","year":"2013","journal-title":"Pak. J. Med. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1086\/318135","article-title":"HIV andLeishmaniaCoinfection: A Review of 91 Cases with Focus on Atypical Locations of Leishmania","volume":"31","author":"Rosenthal","year":"2000","journal-title":"Clin. Infect. Dis."},{"key":"ref_5","first-page":"777","article-title":"American visceral leishmaniasis (kala-azar)","volume":"142","author":"Evans","year":"1985","journal-title":"West. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1016\/0035-9203(91)90293-8","article-title":"Kala-azar in displaced people from southern Sudan: Epidemiological, clinical and therapeutic findings","volume":"85","author":"Zijlstra","year":"1991","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1136\/bmj.303.6798.336","article-title":"Imported and autochthonous kala-azar in France","volume":"303","author":"Jeannel","year":"1991","journal-title":"BMJ"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Petrela, R., Kuneshka, L., Foto, E., Zavalani, F., and Gradoni, L. (2010). Pediatric Visceral Leishmaniasis in Albania: A Retrospective Analysis of 1,210 Consecutive Hospitalized Patients (1995\u20132009). PLoS Negl. Trop. Dis., 4.","DOI":"10.1371\/journal.pntd.0000814"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1080\/02724930123443","article-title":"Visceral leishmaniasis in Omani children: A review","volume":"21","author":"Elnour","year":"2001","journal-title":"Ann. Trop. Paediatr."},{"key":"ref_10","first-page":"154","article-title":"Visceral Leishmaniasis in Children: A Cohort of 120 Patients in a Metropolitan City of Brazil","volume":"53","author":"Rocha","year":"2011","journal-title":"Turk. J. Pediatr."},{"key":"ref_11","first-page":"104","article-title":"Changing Epidemiology: A New Focus of Kala-azar at High-Altitude Garhwal Region of North India","volume":"63","author":"Bhat","year":"2016","journal-title":"J. Trop. Pediatr."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1097\/INF.0000000000001343","article-title":"Clinical and Epidemiologic Features of Visceral Leishmaniasis in Children in Southwestern China: A Retrospective Analysis from 2001 to 2015","volume":"36","author":"Miao","year":"2017","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"141","DOI":"10.2223\/1154","article-title":"Visceral leishmaniasis: Clinical and epidemiological features of children in an endemic area","volume":"80","author":"Queiroz","year":"2004","journal-title":"J. Pediatr."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1136\/jcp.47.6.547","article-title":"Liver morphology and function in visceral leishmaniasis (Kala-azar)","volume":"47","author":"Hashim","year":"1994","journal-title":"J. Clin. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1590\/S0036-46651987000300003","article-title":"Histopathological patterns of the liver involvement in visceral leishmaniasis","volume":"29","author":"Duarte","year":"1987","journal-title":"Rev. Inst. Med. Trop. S\u00e3o Paulo"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1186\/s13071-018-2624-z","article-title":"Histopathological and immunohistochemical characterisation of hepatic granulomas in Leishmania donovani-infected BALB\/c mice: A time-course study","volume":"11","author":"Salguero","year":"2018","journal-title":"Parasites Vectors"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Moore, J.W.J., Beattie, L., Dalton, J., Owens, B.M.J., Maroof, A., Coles, M.C., and Kaye, P.M. (2012). B Cell: T Cell Interactions Occur within Hepatic Granulomas during Experimental Visceral Leishmaniasis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034143"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Khadem, F., Mou, Z., Liu, D., Varikuti, S., Satoskar, A., and Uzonna, J.E. (2014). Deficiency of p110\u03b4 Isoform of the Phosphoinositide 3 Kinase Leads to Enhanced Resistance to Leishmania donovani. PLoS Negl. Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0002951"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1038\/sj.gene.6363660","article-title":"Susceptibility to Leishmania major infection in mice: Multiple loci and heterogeneity of immunopathological phenotypes","volume":"1","author":"Lipoldova","year":"2000","journal-title":"Genes Immun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2560","DOI":"10.1194\/jlr.M026914","article-title":"Hyperlipidemia offers protection against Leishmania donovani infection: Role of membrane cholesterol","volume":"53","author":"Ghosh","year":"2012","journal-title":"J. Lipid Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.4049\/jimmunol.166.3.1912","article-title":"The Hamster as a Model of Human Visceral Leishmaniasis: Progressive Disease and Impaired Generation of Nitric Oxide in the Face of a Prominent Th1-Like Cytokine Response","volume":"166","author":"Melby","year":"2001","journal-title":"J. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Morimoto, A., Omachi, S., Osada, Y., Chambers, J., Uchida, K., Sanjoba, C., Matsumoto, Y., and Goto, Y. (2016). Hemophagocytosis in Experimental Visceral Leishmaniasis by Leishmania donovani. PLoS Negl. Trop. Dis., 10.","DOI":"10.1371\/journal.pntd.0004505"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1542\/pir.21.9.303","article-title":"Hepatomegaly in neonates and children","volume":"21","author":"Wolf","year":"2000","journal-title":"Pediatr. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1186\/s13071-019-3723-1","article-title":"Assessment of histological liver alterations in dogs naturally infected with Leishmania infantum","volume":"12","author":"Lima","year":"2019","journal-title":"Parasites Vectors"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1136\/gut.13.2.147","article-title":"Portal hypertension in kala-azar","volume":"13","author":"Datta","year":"1972","journal-title":"Gut"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"965","DOI":"10.1007\/s13312-010-0162-7","article-title":"Portal hypertension with visceral leishmaniasis","volume":"47","author":"Prasad","year":"2010","journal-title":"Indian Pediatr."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Lahlou, H., Filali, A.B., Alami, M., Amrani, M., Berrady, R., Rabhi, S., and Bono, W. (2011). Visceral leishmaniasis in 26 HIV-negative adults. BMC Res. Notes, 4.","DOI":"10.1186\/1756-0500-4-389"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Lindoso, J.A., Cota, G.F., Da Cruz, A.M., Goto, H., Maia-Elkhoury, A.N.S., Romero, G.A.S., De Sousa-Gomes, M.L., Santos-Oliveira, J.R., and Rabello, A. (2014). Visceral Leishmaniasis and HIV Coinfection in Latin America. PLoS Negl. Trop. Dis., 8.","DOI":"10.1371\/journal.pntd.0003136"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1127","DOI":"10.4269\/ajtmh.16-0940","article-title":"Is Visceral Leishmaniasis Different in Immunocompromised Patients Without Human Immunodeficiency Virus? A Comparative, Multicenter Retrospective Cohort Analysis","volume":"97","author":"Ramos","year":"2017","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"528","DOI":"10.1016\/j.bbrc.2017.06.005","article-title":"B-cell activating factor deficiency suppresses splenomegaly during Leishmania donovani infection","volume":"489","author":"Omachi","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Ishizuka, K., Fujii, W., Azuma, N., Mizobuchi, H., Morimoto, A., Sanjoba, C., Matsumoto, Y., and Goto, Y. (2020). Pathological roles of MRP14 in anemia and splenomegaly during experimental visceral leishmaniasis. PLoS Negl. Trop. Dis., 14.","DOI":"10.1371\/journal.pntd.0008020"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1111\/j.1365-3024.2006.00817.x","article-title":"Immunohistological features of visceral leishmaniasis in BALB\/c mice","volume":"28","author":"Nieto","year":"2006","journal-title":"Parasite Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1002\/hep.27747","article-title":"The significance of nonobstructive sinusoidal dilatation of the liver: Impaired portal perfusion or inflammatory reaction syndrome","volume":"62","author":"Marzano","year":"2015","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1002\/hep.510300148","article-title":"Nitric oxide in liver injury","volume":"30","author":"Clemens","year":"1999","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1220","DOI":"10.1172\/JCI3428","article-title":"Protective role of endogenous carbon monoxide in hepatic microcirculatory dysfunction after hemorrhagic shock in rats","volume":"102","author":"Pannen","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1172\/JCI118300","article-title":"Carbon monoxide: An endogenous modulator of sinusoidal tone in the perfused rat liver","volume":"96","author":"Suematsu","year":"1995","journal-title":"J. Clin. Investig."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Fievez, A.M.D.C., Silva-Freitas, M.L., Sousa, A.D.Q., Santos-Oliveira, J.R., and Da-Cruz, A.M. (2019). Lower levels of leptin are associated with severity parameters in visceral leishmaniasis patients. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0214413"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3391","DOI":"10.2337\/diabetes.51.12.3391","article-title":"Interleukin-6 Induces Cellular Insulin Resistance in Hepatocytes","volume":"51","author":"Senn","year":"2002","journal-title":"Diabetes"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1007\/s00436-007-0464-4","article-title":"Characterization of Leishmania isolates from Nepalese patients with visceral leishmaniasis","volume":"100","author":"Pandey","year":"2007","journal-title":"Parasitol. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"28","DOI":"10.2307\/3274825","article-title":"An Approach toward a Course in the Principles of Parasitism","volume":"44","author":"Huff","year":"1958","journal-title":"J. Parasitol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1590\/S0001-37652003000400006","article-title":"Stereological tools in biomedical research","volume":"75","year":"2003","journal-title":"An. Acad. Bras. Ci\u00eanc."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"110097","DOI":"10.1016\/j.biopha.2020.110097","article-title":"Lipophosphoglycan-3 recombinant protein vaccine controls hepatic parasitism and prevents tissue damage in mice infected by Leishmania infantum chagasi","volume":"126","author":"Bastos","year":"2020","journal-title":"Biomed. Pharmacother."}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/10\/11\/1356\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:19:38Z","timestamp":1760167178000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/10\/11\/1356"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,20]]},"references-count":42,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2021,11]]}},"alternative-id":["pathogens10111356"],"URL":"https:\/\/doi.org\/10.3390\/pathogens10111356","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,20]]}}}