title: Pretreatment with Rho-kinase inhibitor ameliorates lethal endotoxemia-induced liver injury by improving mitochondrial function.
abstract: Rho kinase (ROCK) inhibition has been reported to improve various inflammatory diseases including endotoxemia. Mitochondrial dysfunction might be the key to the pathophysiology of sepsis-induced organ failure. Therefore, this study aimed to explore whether ROCK inhibition protects against the liver injury by regulating mitochondrial function in endotoxemia model mice. The mice were randomly divided into four groups (N=6-8 per group): control, LPS, LPS+Y-27632 (LPS+Y), and LPS+Mito-TEMPO (LPS+M). For induction of endotoxin-induced acute liver injury, the mice were intraperitoneally administered lipopolysaccharide (LPS, 20mg/kg). The ROCK inhibitor Y-27632 (or mitochondrial antioxidant Mito-TEMPO) was intraperitoneally administered at 18 and 1h before injection of LPS. The mice were euthanized 8h after LPS administration. The liver and blood samples were taken and preserved for analysis. Results of this study showed that pretreatment with Y-27632 or Mito-TEMPO significantly attenuated the liver injury as compared to the LPS group. This was confirmed by decreased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, and by reduced hepatocellular apoptosis and histologic damage. Pretreatment with Y-27632 or Mito-TEMPO markedly reduced the LPS-induced inflammatory response and oxidative stress the in liver. Furthermore, it showed similar protective effects on the hepatic mitochondrial function, including an increased activity of complexes I and IV and mitochondrial superoxide dismutase (MnSOD), and an upregulated expression of mtDNA-encoded genes. Taken together, these data demonstrate that Mito-TEMPO can potently inhibit the endotoxin-induced mitochondrial and hepatic abnormalities and indicate that mitochondrial dysfunction might play a key role in the endotoxemia-induced acute liver injury. Moreover, our study shows that ROCK inhibition protects against the endotoxemia-induced liver injury by improving the mitochondrial function.
authors: Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, PR China. Electronic address: renyuding@126.com.
authors: Renyu
authors: R
authors: Ding
authors: Department of Otolaryngology, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, PR China.
authors: Jiali
authors: J
authors: Han
authors: Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, PR China.
authors: Dongmei
authors: D
authors: Zhao
authors: Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, PR China.
authors: Ziwei
authors: Z
authors: Hu
authors: Department of Intensive Care Unit, The First Hospital of China Medical University, Nanjing Bei Street 155, Shenyang 110001, Liaoning Province, PR China. Electronic address: xcma2972@sina.com.
authors: Xiaochun
authors: X
authors: Ma
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001219:Aspartate Aminotransferases / Q000097:blood; D051546:Cyclooxygenase 2 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D019446:Endotoxemia / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D005260:Female; D022781:Hepatocytes / Q000187:drug effects; D006609:High Mobility Group Proteins / Q000235:genetics; D008070:Lipopolysaccharides; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008107:Liver Diseases / Q000097:blood / Q000188:drug therapy* / Q000209:etiology; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000494:pharmacology; D009195:Peroxidase / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D013482:Superoxide Dismutase / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000577:Amides; D000975:Antioxidants; D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D008070:Lipopolysaccharides; C555916:MitoTEMPO; D009943:Organophosphorus Compounds; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C081930:Tfam protein, mouse; C108830:Y 27632; D008315:Malondialdehyde; D009195:Peroxidase; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D013482:Superoxide Dismutase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D054460:rho-Associated Kinases
keywords: Lipopolysaccharide; Liver injury; Mitochondrial dysfunction; Oxidative stress; Rho kinase; Sepsis