Correspondence: Luiz A. R. de Freitas, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Rua Waldemar Falcão, 121, Candeal, Salvador, BA, CEP 40296–710, Brazil. E-mail: lfreitas@bahia.fiocruz.br. (Received 15 February 2012; accepted 1 April 2012) 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 BRUNO SOLANO DE FREITAS SOUZA 1,2 , RAMON CAMPOS NASCIMENTO 3,4 , SHEILLA ANDRADE DE OLIVEIRA 1,5 , JULIANA FRAGA VASCONCELOS 1,2 , CARLA MARTINS KANETO 2 , LIAN FELIPE PAIVA PONTES DE CARVALHO 2 , RICARDO RIBEIRO-DOS-SANTOS 1,2 , MILENA BOTELHO PEREIRA SOARES 1,2 & LUIZ ANTONIO RODRIGUES DE FREITAS 3,4 1 Laboratório de Engenharia Tecidual e Imunofarmacologia, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brazil, 2 Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Salvador, BA, Brazil, 3 Laboratório de Patologia e Biointervenção, Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brazil, 4 Faculdade de Medicina, Universidade Federal da Bahia, Salvador, BA, Brazil, and 5 Laboratório de Imunopatologia e Biologia Molecular, Centro de Pesquisas Aggeu Magalhães, Fundação Oswaldo Cruz, Recife, PE, Brazil 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 transplan- tation 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 concentra- tions, 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 Introduction Acute liver failure (ALF) is caused by liver cell dysfunction, leading to coagulopathy, hepatic encephalopathy and death in previously healthy patients. The main cause of this illness is poisoning with acetaminophen ( N-acetyl-paraaminophen; APAP) through unintentional overdoses or suicide attempts (1). This drug induces severe centrolob- ular hepatocellular necrosis and increases serum transaminase levels, in a dose-dependent man- ner. The extent of APAP-induced hepatic lesions is increased by fasting and alcohol consumption, both in animals and humans (2,3). APAP is metabolized by cytochrome P450 to form N-acetyl- p-benzoquinone imine (NAPQI). This reac- tive metabolite depletes glutathione and covalently binds to cysteine groups on proteins, leading to inhi- bition of mitochondrial respiration, mitochondrial permeability transition, hepatic necrosis and inflam- matory response (4,5). The consequent massive death of hepatocytes is followed by disturbances in the hepatic cycle of urea and an increase in serum Cytotherapy, 2012; 14: 1011–1021 ISSN 1465-3249 print/ISSN 1477-2566 online © 2012 Informa Healthcare DOI: 10.3109/14653249.2012.684445