Transplantation of bone marrow cells decreases tumor necrosis factor-α production and blood-brain barrier permeability and improves survival in a mouse model of acetaminophen-induced acute liver disease.
OBJECTIVE
Acute liver failure (ALF), although rare, remains a rapidly progressive and frequently fatal condition. Acetaminophen (APAP) poisoning induces a massive hepatic necrosis and often leads to death as a result of cerebral edema. Cell-based therapies are currently being investigated for liver injuries. We evaluated the therapeutic potential of transplantation of bone marrow mononuclear cells (BMC) in a mouse model of acute liver injury.


METHODS
ALF was induced in C57Bl/6 mice submitted to an alcoholic diet followed by fasting and injection of APAP. Mice were transplanted with 10(7) BMC obtained from enhanced green fluorescent protein (GFP) transgenic mice.


RESULTS
BMC transplantation caused a significant reduction in APAP-induced mortality. However, no significant differences in serum aminotransferase concentrations, extension of liver necrosis, number of inflammatory cells and levels of cytokines in the liver were found when BMC- and saline-injected groups were compared. Moreover, recruitment of transplanted cells to the liver was very low and no donor-derived hepatocytes were observed. Mice submitted to BMC therapy had some protection against disruption of the blood-brain barrier, despite their hyperammonemia, and serum metalloproteinase (MMP)-9 activity similar to the saline-injected group. Tumor necrosis factor (TNF)-α concentrations were decreased in the serum of BMC-treated mice. This reduction was associated with an early increase in interleukin (IL)-10 mRNA expression in the spleen and bone marrow after BMC treatment.


CONCLUSIONS
BMC transplantation protects mice submitted to high doses of APAP and is a potential candidate for ALF treatment, probably via an immunomodulatory effect on TNF-α production.
Laboratório de Engenharia Tecidual e Imunofarmacologia, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brazil.
Bruno Solano
BS
de Freitas Souza
Ramon Campos
RC
Nascimento
Sheilla Andrade
SA
de Oliveira
Juliana Fraga
JF
Vasconcelos
Carla Martins
CM
Kaneto
Lian Felipe Paiva Pontes
LF
de Carvalho
Ricardo
R
Ribeiro-Dos-Santos
Milena Botelho Pereira
MB
Soares
Luiz Antonio Rodrigues
LA
de Freitas
D000082:Acetaminophen / Q000633:toxicity; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D016026:Bone Marrow Transplantation; D064987:Cell- and Tissue-Based Therapy; D004195:Disease Models, Animal; D016753:Interleukin-10 / Q000378:metabolism; D017114:Liver Failure, Acute / Q000139:chemically induced / Q000628:therapy; D047508:Massive Hepatic Necrosis / Q000139:chemically induced / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D010539:Permeability; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D000082:Acetaminophen