Morphological and molecular pathology of CCL4-induced hepatic fibrosis in connexin43-deficient mice.
Gap junction channels, formed by connexins (Cx), are involved in the maintenance of tissue homeostasis, cell growth, differentiation, and development. Several studies have shown that Cx43 is involved in the control of wound healing in dermal tissue. However, it remains unknown whether Cx43 plays a role in the control of liver fibrogenesis. Our study investigated the roles of Cx43 heterologous deletion on carbon tetrachloride (CCl(4))-induced hepatic fibrosis in mice. We administered CCl(4) to both Cx43-deficient (Cx43(+/-)) and wild-type mice and examined hepatocellular injury and collagen deposition by histological and ultrastructural analyses. Serum biochemical analysis was performed to quantify liver injury. Hepatocyte proliferation was analyzed immunohistochemically. Protein and messenger RNA (mRNA) expression of liver connexins were evaluated using immunohistochemistry as well as immunoblotting analysis and quantitative real-time PCR. We demonstrated that Cx43(+/-) mice developed excessive liver fibrosis compared with wild-type mice after CCl(4) -induced chronic hepatic injury, with thick and irregular collagen fibers. Histopathological evaluation showed that Cx43(+/-) mice present less necroinflammatory lesions in liver parenchyma and consequent reduction of serum aminotransferase activity. Hepatocyte cell proliferation was reduced in Cx43(+/-) mice. There was no difference in Cx32 and Cx26 protein or mRNA expression in fibrotic mice. Protein expression of Cx43 increased in CCl(4)-treated mice, although with aberrant protein location on cytoplasm of perisinusoidal cells. Our results demonstrate that Cx43 plays an important role in the control and regulation of hepatic fibrogenesis.
Cogliati
Bruno
B
Department of Pathology, School of Veterinary Medicine and Animal Science, University of Sao Paulo, Sao Paulo 05508-900, Brazil. bcogliati@usp.br
Da Silva
Tereza Cristina
TC
Aloia
Thiago Pinheiro Arrais
TP
Chaible
Lucas Martins
LM
Real-Lima
Mirela Aline
MA
Sanches
Daniel Soares
DS
Matsuzaki
Patrícia
P
Hernandez-Blazquez
Francisco Javier
FJ
Dagli
Maria Lúcia Zaidan
ML
D000818:Animals; D054407:Chemokine CCL4 / Q000633:toxicity*; D018031:Connexin 43 / Q000172:deficiency*; D008099:Liver / Q000473:pathology*; D008103:Liver Cirrhosis / Q000139:chemically induced*; D051379:Mice; D057089:Pathology, Molecular
D054407:Chemokine CCL4; D018031:Connexin 43