{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T23:58:33Z","timestamp":1784591913071,"version":"3.55.0"},"reference-count":23,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T00:00:00Z","timestamp":1529020800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,6,15]],"date-time":"2018-06-15T00:00:00Z","timestamp":1529020800000},"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>Despite being a cardinal experimental model, the induction of cirrhosis in rats by repeated exposure to carbon tetrachloride (CCl4) has low reproducibility. Here, we compared two models of cirrhosis induced by orogastric administration of CCl4 once (CCl4-1xWk) or twice a week (CCl4-2xWk) for 12 weeks in male Sprague-Dawley rats. Control rats received water instead of CCl4. Both CCl4 protocols similarly attenuated body weight gain (p\u2009&lt;\u20090.01 vs. Control). Although both CCl4 protocols increased hepatic fibrosis, portal hypertension and splenomegaly, the magnitude of these alterations was higher and more consistent in CCl4-2xWk rats. Importantly, two CCl4-1xWk rats did not develop cirrhosis versus a 100% yield of cirrhosis in CCl4-2xWk rats. The CCl4-2xWk protocol consistently induced liver atrophy together with hematological, biochemical and coagulation abnormalities characteristic of advanced cirrhosis that were absent in CCl4-1xWk rats. Ascites occurred in 20% and 80% of rats in theCCl4-1xWk and CCl4-2xWk groups (p\u2009&lt;\u20090.01). All rats showed normal renal function, arterial blood gases and stable systemic hemodynamics. The total dose of CCl4 and mortality rate were similar in both protocols. The CCl4-2xWk protocol, therefore, was highly reproducible and effective for the induction of experimental cirrhosis within a confined time, representing a valuable advance for liver research.<\/jats:p>","DOI":"10.1038\/s41598-018-27427-9","type":"journal-article","created":{"date-parts":[[2018,6,11]],"date-time":"2018-06-11T08:50:42Z","timestamp":1528707042000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["Comparison of Two Protocols of Carbon Tetrachloride-Induced Cirrhosis in Rats \u2013 Improving Yield and Reproducibility"],"prefix":"10.1038","volume":"8","author":[{"given":"Jos\u00e9 I","family":"Fortea","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Fern\u00e1ndez-Mena","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Puerto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Ripoll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Almagro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Ba\u00f1ares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 M.","family":"Bell\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael","family":"Ba\u00f1ares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8903-7288","authenticated-orcid":false,"given":"Javier","family":"Vaquero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,6,15]]},"reference":[{"key":"27427_CR1","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1172\/JCI30542","volume":"117","author":"JP Iredale","year":"2007","unstructured":"Iredale, J. P. Models of liver fibrosis: exploring the dynamic nature of inflammation and repair in a solid organ. J. Clin. Invest. 117, 539\u2013548 (2007).","journal-title":"J. Clin. Invest."},{"key":"27427_CR2","first-page":"G52","volume":"244","author":"J Vorobioff","year":"1983","unstructured":"Vorobioff, J., Bredfeldt, J. E. & Groszmann, R. J. Hyperdynamic circulation in portal-hypertensive rat model: a primary factor for maintenance of chronic portal hypertension. Am. J. Physiol. 244, G52\u201357 (1983).","journal-title":"Am. J. Physiol."},{"key":"27427_CR3","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1038\/252049a0","volume":"252","author":"I Okazaki","year":"1974","unstructured":"Okazaki, I. & Maruyama, K. Collagenase activity in experimental hepatic fibrosis. Nature 252, 49\u201350 (1974).","journal-title":"Nature"},{"key":"27427_CR4","doi-asserted-by":"publisher","first-page":"6577","DOI":"10.3748\/wjg.v12.i41.6577","volume":"12","author":"J-G Abraldes","year":"2006","unstructured":"Abraldes, J.-G., Pasar\u00edn, M. & Garc\u00eda-Pag\u00e1n, J.-C. Animal models of portal hypertension. World J. Gastroenterol. 12, 6577\u20136584 (2006).","journal-title":"World J. Gastroenterol."},{"key":"27427_CR5","doi-asserted-by":"publisher","first-page":"G449","DOI":"10.1152\/ajpgi.00199.2012","volume":"304","author":"Y Liu","year":"2013","unstructured":"Liu, Y. et al. Animal models of chronic liver diseases. Am. J. Physiol. Gastrointest. Liver Physiol. 304, G449\u2013468 (2013).","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"27427_CR6","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/0016-5085(91)90221-6","volume":"100","author":"BA Runyon","year":"1991","unstructured":"Runyon, B. A., Sugano, S., Kanel, G. & Mellencamp, M. A. A rodent model of cirrhosis, ascites, and bacterial peritonitis. Gastroenterology 100, 489\u2013493 (1991).","journal-title":"Gastroenterology"},{"key":"27427_CR7","doi-asserted-by":"crossref","first-page":"1183","DOI":"10.1016\/S0016-5085(82)80126-1","volume":"83","author":"E Proctor","year":"1982","unstructured":"Proctor, E. & Chatamra, K. High yield micronodular cirrhosis in the rat. Gastroenterology 83, 1183\u20131190 (1982).","journal-title":"Gastroenterology"},{"key":"27427_CR8","first-page":"283","volume":"62","author":"K Chatamra","year":"1981","unstructured":"Chatamra, K. & Proctor, E. Phenobarbitone-induced enlargement of the liver in the rat: its relationship to carbon tetrachloride-induced cirrhosis. Br. J. Exp. Pathol. 62, 283\u2013288 (1981).","journal-title":"Br. J. Exp. Pathol."},{"key":"27427_CR9","doi-asserted-by":"publisher","first-page":"6943","DOI":"10.3748\/wjg.14.6943","volume":"14","author":"J-M Regimbeau","year":"2008","unstructured":"Regimbeau, J.-M., Fuks, D., Kohneh-Shahri, N., Terris, B. & Soubrane, O. Restrictive model of compensated carbon tetrachloride-induced cirrhosis in rats. World J. Gastroenterol. 14, 6943\u20136947 (2008).","journal-title":"World J. Gastroenterol."},{"key":"27427_CR10","doi-asserted-by":"publisher","first-page":"1148","DOI":"10.1111\/j.1440-1746.2006.04553.x","volume":"22","author":"L Desmyter","year":"2007","unstructured":"Desmyter, L. et al. Rating of CCl(4)-induced rat liver fibrosis by blood serum glycomics. J. Gastroenterol. Hepatol. 22, 1148\u20131154 (2007).","journal-title":"J. Gastroenterol. Hepatol."},{"key":"27427_CR11","doi-asserted-by":"publisher","first-page":"2481","DOI":"10.1172\/JCI117617","volume":"94","author":"H Masuda","year":"1994","unstructured":"Masuda, H., Fukumoto, M., Hirayoshi, K. & Nagata, K. Coexpression of the collagen-binding stress protein HSP47 gene and the alpha 1(I) and alpha 1(III) collagen genes in carbon tetrachloride-induced rat liver fibrosis. J. Clin. Invest. 94, 2481\u20132488 (1994).","journal-title":"J. Clin. Invest."},{"key":"27427_CR12","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1002\/hep.510280308","volume":"28","author":"P Sogni","year":"1998","unstructured":"Sogni, P. et al. Beneficial hemodynamic effects of bosentan, a mixed ET(A) and ET(B) receptor antagonist, in portal hypertensive rats. Hepatol. Baltim. Md 28, 655\u2013659 (1998).","journal-title":"Hepatol. Baltim. Md"},{"key":"27427_CR13","first-page":"279","volume":"152","author":"YJ Wang","year":"1998","unstructured":"Wang, Y. J. et al. Two novel antifibrotics, HOE 077 and Safironil, modulate stellate cell activation in rat liver injury: differential effects in males and females. Am. J. Pathol. 152, 279\u2013287 (1998).","journal-title":"Am. J. Pathol."},{"key":"27427_CR14","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.clnu.2007.01.008","volume":"26","author":"R Bartol\u00ed","year":"2007","unstructured":"Bartol\u00ed, R. et al. Effect of the administration of fermentable and non-fermentable dietary fibre on intestinal bacterial translocation in ascitic cirrhotic rats. Clin. Nutr. Edinb. Scotl. 26, 383\u2013387 (2007).","journal-title":"Clin. Nutr. Edinb. Scotl."},{"key":"27427_CR15","doi-asserted-by":"publisher","first-page":"1957","DOI":"10.1023\/A:1026649730012","volume":"44","author":"C Guarner","year":"1999","unstructured":"Guarner, C., Runyon, B. A., Heck, M., Young, S. & Sheikh, M. Y. Effect of long-term trimethoprim-sulfamethoxazole prophylaxis on ascites formation, bacterial translocation, spontaneous bacterial peritonitis, and survival in cirrhotic rats. Dig. Dis. Sci. 44, 1957\u20131962 (1999).","journal-title":"Dig. Dis. Sci."},{"key":"27427_CR16","first-page":"1648","volume":"35","author":"JM Llovet","year":"1994","unstructured":"Llovet, J. M. et al. Bacterial translocation in cirrhotic rats. Its role in the development of spontaneous bacterial peritonitis. Gut 35, 1648\u20131652 (1994).","journal-title":"Its role in the development of spontaneous bacterial peritonitis. Gut"},{"key":"27427_CR17","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1002\/hep.510310109","volume":"31","author":"M P\u00e9rez-Paramo","year":"2000","unstructured":"P\u00e9rez-Paramo, M. et al. Effect of propranolol on the factors promoting bacterial translocation in cirrhotic rats with ascites. Hepatol. Baltim. Md 31, 43\u201348 (2000).","journal-title":"Hepatol. Baltim. Md"},{"key":"27427_CR18","doi-asserted-by":"publisher","first-page":"2086","DOI":"10.1002\/hep.23961","volume":"52","author":"M \u00dabeda","year":"2010","unstructured":"\u00dabeda, M. et al. Critical role of the liver in the induction of systemic inflammation in rats with preascitic cirrhosis. Hepatol. Baltim. Md 52, 2086\u20132095 (2010).","journal-title":"Hepatol. Baltim. Md"},{"key":"27427_CR19","first-page":"237","volume":"117","author":"C Constandinou","year":"2005","unstructured":"Constandinou, C., Henderson, N. & Iredale, J. P. Modeling liver fibrosis in rodents. Methods Mol. Med. 117, 237\u2013250 (2005).","journal-title":"Methods Mol. Med."},{"key":"27427_CR20","first-page":"521","volume":"36","author":"RO Recknagel","year":"1960","unstructured":"Recknagel, R. O. & Litteria, M. Biochemical changes in carbon tetrachloride fatty liver: concentration of carbon tetrachloride in liver and blood. Am. J. Pathol. 36, 521\u2013531 (1960).","journal-title":"Am. J. Pathol."},{"key":"27427_CR21","first-page":"102","volume":"38","author":"JI Fortea","year":"2018","unstructured":"Fortea, J. I. et al. Enoxaparin does not ameliorate liver fibrosis or portal hypertension in rats with advanced cirrhosis. Liver Int. Off. J. Int. Assoc. Study Liver 38, 102\u2013112 (2018).","journal-title":"Liver Int. Off. J. Int. Assoc. Study Liver"},{"key":"27427_CR22","doi-asserted-by":"publisher","first-page":"G301","DOI":"10.1152\/ajpgi.00010.2015","volume":"309","author":"DM Tripathi","year":"2015","unstructured":"Tripathi, D. M. et al. Metformin reduces hepatic resistance and portal pressure in cirrhotic rats. Am. J. Physiol. Gastrointest. Liver Physiol. 309, G301\u2013309 (2015).","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"27427_CR23","unstructured":"National Toxicology Program. NTP 12th Report on Carcinogens. Rep. Carcinog. Carcinog. Profiles 12, iii-499 (2011)."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27427-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27427-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27427-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T06:27:24Z","timestamp":1671604044000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27427-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,15]]},"references-count":23,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["27427"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-27427-9","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,15]]},"assertion":[{"value":"8 February 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 June 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 June 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"9163"}}