{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T17:59:09Z","timestamp":1778781549774,"version":"3.51.4"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T00:00:00Z","timestamp":1509062400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,10,27]],"date-time":"2017-10-27T00:00:00Z","timestamp":1509062400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>We investigated serial changes of the Kupffer cell (KC) function and hepatic oxygen saturation (sO<jats:sub>2<\/jats:sub>) using contrast-enhanced ultrasound imaging (CEUS) and photoacoustic imaging (PAI) in preneoplastic changes during cholangiocarcinogenesis induced by obstructive cholangitis and N-nitrosodimethylamine in a mouse model. The CEUS and PAI were performed to assess Sonazoid contrast agent uptake by KC and changes in the sO<jats:sub>2<\/jats:sub> of liver parenchyma. An extensive bile ductular reaction, cystic dilatation, and epithelial hyperplasia with dysplastic changes were noted in the experimental group. During the preneoplastic changes, the parenchymal echogenicity on the Kupffer-phase of CEUS was continuously decreased in the experimental group, and which means that the Sonazoid phagocytosis by KC was decreased. The number of KCs was increased in the CD68 analysis, indicating functionally impaired KCs. There was a simultaneous serial decrease in sO<jats:sub>2<\/jats:sub> on PAI measurement of the experimental group during the preneoplastic changes. The experimental group also showed significantly higher expression of hypoxia-inducible factor-1\u03b1 and vascular endothelial growth factor protein. Our study demonstrated that KC dysfunction and hypoxic environmental changes were the factors influencing preneoplastic change during cholangiocarcinogenesis, and we could non-invasively monitor these changes using CEUS and PAI.<\/jats:p>","DOI":"10.1038\/s41598-017-14218-x","type":"journal-article","created":{"date-parts":[[2017,10,23]],"date-time":"2017-10-23T16:12:15Z","timestamp":1508775135000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Imaging Monitoring of Kupffer Cell Function and Hepatic Oxygen Saturation in Preneoplastic Changes During Cholangiocarcinogenesis"],"prefix":"10.1038","volume":"7","author":[{"given":"Seunghyun","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jung Hoon","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeong Hwa","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoh","family":"Zen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joon Koo","family":"Han","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,10,27]]},"reference":[{"key":"14218_CR1","doi-asserted-by":"publisher","first-page":"1303","DOI":"10.1016\/S0140-6736(05)67530-7","volume":"366","author":"SA Khan","year":"2005","unstructured":"Khan, S. A., Thomas, H. C., Davidson, B. R. & Taylor-Robinson, S. D. Cholangiocarcinoma. Lancet \n                           366, 1303\u20131314 (2005).","journal-title":"Lancet"},{"key":"14218_CR2","doi-asserted-by":"publisher","first-page":"308","DOI":"10.1002\/hep.22310","volume":"48","author":"B Blechacz","year":"2008","unstructured":"Blechacz, B. & Gores, G. J. Cholangiocarcinoma: advances in pathogenesis, diagnosis, and treatment. Hepatology \n                           48, 308\u2013321 (2008).","journal-title":"Hepatology"},{"key":"14218_CR3","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.dld.2012.10.008","volume":"45","author":"S De Minicis","year":"2013","unstructured":"De Minicis, S. et al. Liver carcinogenesis: rodent models of hepatocarcinoma and cholangiocarcinoma. Dig Liver Dis \n                           45, 450\u2013459 (2013).","journal-title":"Dig Liver Dis"},{"key":"14218_CR4","doi-asserted-by":"publisher","first-page":"861","DOI":"10.1007\/s00423-012-0943-7","volume":"397","author":"L Sibulesky","year":"2012","unstructured":"Sibulesky, L., Nguyen, J. & Patel, T. Preneoplastic conditions underlying bile duct cancer. Langenbecks Arch Surg \n                           397, 861\u2013867 (2012).","journal-title":"Langenbecks Arch Surg"},{"key":"14218_CR5","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1097\/PAS.0b013e3181bc96f9","volume":"34","author":"JT Lewis","year":"2010","unstructured":"Lewis, J. T., Talwalkar, J. A., Rosen, C. B., Smyrk, T. C. & Abraham, S. C. Precancerous Bile Duct Pathology in End-stage Primary Sclerosing Cholangitis, With and Without Cholangiocarcinoma. Am J Surg Pathol \n                           34, 27\u201334 (2010).","journal-title":"Am J Surg Pathol"},{"key":"14218_CR6","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1111\/j.1440-1827.2010.02543.x","volume":"60","author":"Y Nakanuma","year":"2010","unstructured":"Nakanuma, Y. A novel approach to biliary tract pathology based on similarities to pancreatic counterparts: Is the biliary tract an incomplete pancreas? Pathology International \n                           60, 419\u2013429 (2010).","journal-title":"Pathology International"},{"key":"14218_CR7","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1186\/1755-1536-6-19","volume":"6","author":"C Liedtke","year":"2013","unstructured":"Liedtke, C. et al. Experimental liver fibrosis research: update on animal models, legal issues and translational aspects. Fibrogenesis Tissue Repair \n                           6, 19 (2013).","journal-title":"Fibrogenesis Tissue Repair"},{"key":"14218_CR8","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1093\/toxsci\/kfl173","volume":"96","author":"RA Roberts","year":"2007","unstructured":"Roberts, R. A. et al. Role of the Kupffer cell in mediating hepatic toxicity and carcinogenesis. Toxicol Sci \n                           96, 2\u201315 (2007).","journal-title":"Toxicol Sci"},{"key":"14218_CR9","doi-asserted-by":"publisher","first-page":"258","DOI":"10.1055\/s-0030-1255355","volume":"30","author":"O Rosmorduc","year":"2010","unstructured":"Rosmorduc, O. & Housset, C. Hypoxia: A Link between Fibrogenesis, Angiogenesis, and Carcinogenesis in Liver Disease. Semin Liver Dis \n                           30, 258\u2013270 (2010).","journal-title":"Semin Liver Dis"},{"key":"14218_CR10","doi-asserted-by":"publisher","first-page":"6036","DOI":"10.3748\/wjg.14.6036","volume":"14","author":"T Tsujimoto","year":"2008","unstructured":"Tsujimoto, T. et al. Decreased phagocytic activity of Kupffer cells in a rat nonalcoholic steatohepatitis model. World J Gastroenterol \n                           14, 6036\u20136043 (2008).","journal-title":"World J Gastroenterol"},{"key":"14218_CR11","doi-asserted-by":"publisher","first-page":"4191","DOI":"10.3748\/wjg.v17.i37.4191","volume":"17","author":"Y Miyata","year":"2011","unstructured":"Miyata, Y., Miyahara, T. & Moriyasu, F. Decreased accumulation of ultrasound contrast in the liver of nonalcoholic steatohepatitis rat model. World J Gastroenterol \n                           17, 4191\u20134198 (2011).","journal-title":"World J Gastroenterol"},{"key":"14218_CR12","doi-asserted-by":"publisher","first-page":"e0153532","DOI":"10.1371\/journal.pone.0153532","volume":"11","author":"F Raes","year":"2016","unstructured":"Raes, F. et al. High Resolution Ultrasound and Photoacoustic Imaging of Orthotopic Lung Cancer in Mice: New Perspectives for Onco-Pharmacology. Plos One \n                           11, e0153532 (2016).","journal-title":"Plos One"},{"key":"14218_CR13","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/j.soc.2008.12.001","volume":"18","author":"K Bickenbach","year":"2009","unstructured":"Bickenbach, K., Galka, E. & Roggin, K. K. Molecular mechanisms of cholangiocarcinogenesis: are biliary intraepithelial neoplasia and intraductal papillary neoplasms of the bile duct precursors to cholangiocarcinoma? Surg Oncol Clin N Am \n                           18, 215\u2013224 (2009).","journal-title":"Surg Oncol Clin N Am"},{"key":"14218_CR14","unstructured":"Nguyen-Lefebvre, A. T. & Horuzsko, A. Kupffer Cell Metabolism and Function. J Enzymol Metab 1 (2015)."},{"key":"14218_CR15","doi-asserted-by":"publisher","first-page":"774","DOI":"10.1007\/s00109-005-0678-9","volume":"83","author":"JM Peters","year":"2005","unstructured":"Peters, J. M., Cheung, C. & Gonzalez, F. J. Peroxisome proliferator-activated receptor-alpha and liver cancer: where do we stand? J Mol Med (Berl) \n                           83, 774\u2013785 (2005).","journal-title":"J Mol Med (Berl)"},{"key":"14218_CR16","doi-asserted-by":"publisher","first-page":"3977","DOI":"10.1158\/0008-5472.CAN-12-0938","volume":"72","author":"J Wu","year":"2012","unstructured":"Wu, J. et al. The proinflammatory myeloid cell receptor TREM-1 controls Kupffer cell activation and development of hepatocellular carcinoma. Cancer Res \n                           72, 3977\u20133986 (2012).","journal-title":"Cancer Res"},{"key":"14218_CR17","doi-asserted-by":"publisher","first-page":"812","DOI":"10.1172\/JCI66776","volume":"124","author":"N Gul","year":"2014","unstructured":"Gul, N. et al. Macrophages eliminate circulating tumor cells after monoclonal antibody therapy. J Clin Invest \n                           124, 812\u2013823 (2014).","journal-title":"J Clin Invest"},{"key":"14218_CR18","doi-asserted-by":"crossref","unstructured":"Inoue, T. et al. Kupffer phase image of Sonazoid-enhanced US is useful in predicting a hypervascularization of non-hypervascular hypointense hepatic lesions detected on Gd-EOB-DTPA-enhanced MRI: a multicenter retrospective study. J Gastroenterol \n                           51 (2016).","DOI":"10.1007\/s00535-015-1094-8"},{"key":"14218_CR19","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.ultrasmedbio.2006.08.008","volume":"33","author":"K Yanagisawa","year":"2007","unstructured":"Yanagisawa, K., Moriyasu, F., Miyahara, T., Yuki, M. & Iijima, H. Phagocytosis of ultrasound contrast agent microbubbles by Kupffer cells. Ultrasound Med Biol \n                           33, 318\u2013325 (2007).","journal-title":"Ultrasound Med Biol"},{"key":"14218_CR20","doi-asserted-by":"publisher","first-page":"2461","DOI":"10.1016\/j.ultrasmedbio.2017.05.022","volume":"43","author":"S Lee","year":"2017","unstructured":"Lee, S., Kim, J. H., Lee, J. H. & Choi, S. Y. Image Monitoring of the Impaired Phagocytic Activity of Kupffer Cells and Liver Oxygen Saturation in a Mouse Cholangitis Model Using Contrast-Enhanced Ultrasound Imaging and Photoacoustic Imaging. Ultrasound Med Biol \n                           43, 2461\u20132468 (2017).","journal-title":"Ultrasound Med Biol"},{"key":"14218_CR21","doi-asserted-by":"publisher","first-page":"722","DOI":"10.1111\/j.1872-034X.2007.00130.x","volume":"37","author":"H Iijima","year":"2007","unstructured":"Iijima, H. et al. Decrease in accumulation of ultrasound contrast microbubbles in non-alcoholic steatohepatitis. Hepatol Res \n                           37, 722\u2013730 (2007).","journal-title":"Hepatol Res"},{"key":"14218_CR22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/emm.2004.1","volume":"36","author":"JW Lee","year":"2004","unstructured":"Lee, J. W., Bae, S. H., Jeong, J. W., Kim, S. H. & Kim, K. W. Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions. Exp Mol Med \n                           36, 1\u201312 (2004).","journal-title":"Exp Mol Med"},{"key":"14218_CR23","doi-asserted-by":"publisher","first-page":"728","DOI":"10.3892\/ijo.2015.3056","volume":"47","author":"Q Tian","year":"2015","unstructured":"Tian, Q. et al. Overexpression of hypoxia-inducible factor 1 alpha induces migration and invasion through Notch signaling. International Journal of Oncology \n                           47, 728\u2013738 (2015).","journal-title":"International Journal of Oncology"},{"key":"14218_CR24","doi-asserted-by":"publisher","first-page":"604","DOI":"10.7150\/thno.7996","volume":"4","author":"M Gerling","year":"2014","unstructured":"Gerling, M. et al. Real-time assessment of tissue hypoxia in vivo with combined photoacoustics and high-frequency ultrasound. Theranostics \n                           4, 604\u2013613 (2014).","journal-title":"Theranostics"},{"key":"14218_CR25","doi-asserted-by":"publisher","first-page":"110","DOI":"10.1148\/radiol.14140654","volume":"275","author":"LJ Rich","year":"2015","unstructured":"Rich, L. J. & Seshadri, M. Photoacoustic imaging of vascular hemodynamics: validation with blood oxygenation level-dependent MR imaging. Radiology \n                           275, 110\u2013118 (2015).","journal-title":"Radiology"},{"key":"14218_CR26","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1088\/0031-9155\/52\/1\/010","volume":"52","author":"J Laufer","year":"2007","unstructured":"Laufer, J., Delpy, D., Elwell, C. & Beard, P. Quantitative spatially resolved measurement of tissue chromophore concentrations using photoacoustic spectroscopy: application to the measurement of blood oxygenation and haemoglobin concentration. Phys Med Biol \n                           52, 141\u2013168 (2007).","journal-title":"Phys Med Biol"},{"issue":"378\u2013388","key":"14218_CR27","first-page":"388 e371","volume":"141","author":"H Yang","year":"2011","unstructured":"Yang, H. et al. A mouse model of cholestasis-associated cholangiocarcinoma and transcription factors involved in progression. Gastroenterology \n                           141(378\u2013388), 388 e371\u2013374 (2011).","journal-title":"Gastroenterology"},{"key":"14218_CR28","first-page":"1047","volume":"6","author":"J Josko","year":"2000","unstructured":"Josko, J., Gwozdz, B., Jedrzejowska-Szypulka, H. & Hendryk, S. Vascular endothelial growth factor (VEGF) and its effect on angiogenesis. Med Sci Monit \n                           6, 1047\u20131052 (2000).","journal-title":"Med Sci Monit"},{"key":"14218_CR29","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1038\/nrgastro.2016.51","volume":"13","author":"JM Banales","year":"2016","unstructured":"Banales, J. M. et al. Expert consensus document: Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA). Nat Rev Gastroenterol Hepatol \n                           13, 261\u2013280 (2016).","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"14218_CR30","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1111\/j.1872-034X.2010.00670.x","volume":"40","author":"S Yoshikawa","year":"2010","unstructured":"Yoshikawa, S. et al. Crucial role of impaired Kupffer cell phagocytosis on the decreased Sonazoid-enhanced echogenicity in a liver of a nonalchoholic steatohepatitis rat model. Hepatol Res \n                           40, 823\u2013831 (2010).","journal-title":"Hepatol Res"},{"key":"14218_CR31","doi-asserted-by":"publisher","first-page":"G582","DOI":"10.1152\/ajpgi.90368.2008","volume":"296","author":"JO Moon","year":"2009","unstructured":"Moon, J. O., Welch, T. P., Gonzalez, F. J. & Copple, B. L. Reduced liver fibrosis in hypoxia-inducible factor-1alpha-deficient mice. Am J Physiol Gastrointest Liver Physiol \n                           296, G582\u2013592 (2009).","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"14218_CR32","doi-asserted-by":"publisher","first-page":"956","DOI":"10.1007\/s00259-015-3009-6","volume":"42","author":"C Yip","year":"2015","unstructured":"Yip, C., Blower, P. J., Goh, V., Landau, D. B. & Cook, G. J. Molecular imaging of hypoxia in non-small-cell lung cancer. Eur J Nucl Med Mol Imaging \n                           42, 956\u2013976 (2015).","journal-title":"Eur J Nucl Med Mol Imaging"},{"key":"14218_CR33","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-14-692","volume":"14","author":"CN Fatema","year":"2014","unstructured":"Fatema, C. N. et al. Dual tracer evaluation of dynamic changes in intratumoral hypoxic and proliferative states after radiotherapy of human head and neck cancer xenografts using radiolabeled FMISO and FLT. Bmc Cancer \n                           14, 692 (2014).","journal-title":"Bmc Cancer"},{"key":"14218_CR34","doi-asserted-by":"publisher","first-page":"602","DOI":"10.1098\/rsfs.2011.0028","volume":"1","author":"P Beard","year":"2011","unstructured":"Beard, P. Biomedical photoacoustic imaging. Interface Focus \n                           1, 602\u2013631 (2011).","journal-title":"Interface Focus"},{"key":"14218_CR35","doi-asserted-by":"publisher","first-page":"824","DOI":"10.1016\/j.ultrasmedbio.2007.11.006","volume":"34","author":"PC Sontum","year":"2008","unstructured":"Sontum, P. C. Physicochemical characteristics of Sonazoid (TM), a new contrast agent for ultrasound imaging. Ultrasound in Medicine and Biology \n                           34, 824\u2013833 (2008).","journal-title":"Ultrasound in Medicine and Biology"},{"key":"14218_CR36","doi-asserted-by":"publisher","first-page":"1819","DOI":"10.1016\/j.ultrasmedbio.2009.05.013","volume":"35","author":"S Shunichi","year":"2009","unstructured":"Shunichi, S., Hiroko, I., Fuminori, M. & Waki, H. Definition of Contrast Enhancement Phases of the Liver Using a Perfluoro-Based Microbubble Agent, Perflubutane Microbubbles. Ultrasound in Medicine and Biology \n                           35, 1819\u20131827 (2009).","journal-title":"Ultrasound in Medicine and Biology"},{"key":"14218_CR37","doi-asserted-by":"publisher","first-page":"529","DOI":"10.7863\/jum.2012.31.4.529","volume":"31","author":"K Sugimoto","year":"2012","unstructured":"Sugimoto, K. et al. Comparison of Kupffer-phase Sonazoid-enhanced sonography and hepatobiliary-phase gadoxetic acid-enhanced magnetic resonance imaging of hepatocellular carcinoma and correlation with histologic grading. J Ultrasound Med \n                           31, 529\u2013538 (2012).","journal-title":"J Ultrasound Med"},{"key":"14218_CR38","doi-asserted-by":"publisher","first-page":"1749","DOI":"10.1111\/j.1440-1746.2011.06790.x","volume":"26","author":"M Miyazaki","year":"2011","unstructured":"Miyazaki, M. et al. Contrast-enhanced ultrasonography using Sonazoid to evaluate changes in hepatic hemodynamics in acute liver injury. J Gastroen Hepatol \n                           26, 1749\u20131756 (2011).","journal-title":"J Gastroen Hepatol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14218-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14218-x","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14218-x.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T12:49:37Z","timestamp":1671799777000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-14218-x"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,10,27]]},"references-count":38,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["14218"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-14218-x","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,10,27]]},"assertion":[{"value":"4 April 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 October 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 October 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"14203"}}