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

Abstract

Background aims. 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 10⁷ 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.

Key Words::

• acetaminophen
• acute liver failure
• bone marrow mononuclear cells
• brain edema
• cell therapy
• tumor necrosis factor

Acknowledgments

The authors would like to acknowledge Dr Washington Luis Conrado dos Santos for his comments and discussions; Adriano Alcântara, Joselli Santos Silva, Elton Sá Barreto and Carine Machado Azevedo for technical assistance; CNPq, FINEP, MCT and FAPESB for financial support; LACEN, Salvador, BA, for transaminase evaluation; and the Laboratory of Clinical Analysis of the Hospital São Rafael, Salvador, BA, for assessment of serum ammonia.

Conflict of interest statement: The authors claim they have no conflict of interest in this study.