A novel model of CCl4-induced cirrhosis with ascites in the mouse.
OBJECTIVE
The current approaches to study the molecular mechanisms involved in the pathophysiology of liver diseases often rely on the use of transgenic mice. However, experimental models of decompensated cirrhosis have not been clearly established in mice. Thus, we aimed to set an efficient and well-tolerated protocol to induce cirrhosis in mice able to progress up to the ascitic stage.


METHODS
C57BL/6N mice received CCl(4) subcutaneously, intraperitoneally or by inhalation. In the latter group, gaseous CCl(4) was administered according to three different schedules: increasing exposure times, twice weekly (traditional protocol; TP), short inhalation cycles, twice or three times weekly.


RESULTS
Portal hypertension, sodium retention, and ascites developed in all groups between 11 and 15 weeks. Mortality reached 70% in the TP group, but it was only 0-10% with all other protocols. All the inhalation groups had significantly more ascites at sacrifice than those receiving CCl(4) subcutaneously and intraperitoneally. Extensive abdominal adhesions and evidence of enhanced hepatic inflammation, as suggested by the increased gene expression of pro-inflammatory cytokines in liver tissue, were found in the intraperitoneal group, while large granulomas at the injection site and marked neutrophil infiltration of lungs developed in the subcutaneous group. No extra-hepatic damage could be detected in mice inhaling CCl(4).


CONCLUSIONS
The use of short cycles of CCl(4) inhalation represents a novel, safe, and effective method to induce decompensated cirrhosis in mice. Intraperitoneal CCl(4) leads instead to abdominal adhesions precluding a correct evaluation of ascites, while subcutaneous CCl(4) causes an unwanted systemic inflammatory response.
Domenicali
Marco
M
Department of Clinical Medicine, Alma Mater Studiorum University of Bologna, Azienda Ospedaliera-Universitaria Policlinico S. Orsola-Malpighi, Via Massarenti 9, 40138 Bologna, Italy.
Caraceni
Paolo
P
Giannone
Ferdinando
F
Baldassarre
Maurizio
M
Lucchetti
Giovanna
G
Quarta
Carmelo
C
Patti
Corrado
C
Catani
Lucia
L
Nanni
Cristina
C
Lemoli
Roberto M
RM
Bernardi
Mauro
M
D000280:Administration, Inhalation; D000818:Animals; D001201:Ascites / Q000139:chemically induced / Q000503:physiopathology; D002251:Carbon Tetrachloride / Q000008:administration & dosage / Q000633:toxicity*; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D006975:Hypertension, Portal / Q000139:chemically induced; D018836:Inflammation Mediators / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007279:Injections, Subcutaneous; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D012964:Sodium / Q000378:metabolism; D000267:Tissue Adhesions / Q000139:chemically induced / Q000473:pathology
D016207:Cytokines; D018836:Inflammation Mediators; D012964:Sodium; D002251:Carbon Tetrachloride