title: Effects of Tocilizumab on Experimental Severe Acute Pancreatitis and Associated Acute Lung Injury.
abstract: To examine the therapeutic effects of tocilizumab, an antibody against interleukin-6 receptor, on experimental severe acute pancreatitis and associated acute lung injury. The optimal dose of tocilizumab and the activation of interleukin-6 inflammatory signaling were also investigated.
  
  
  
  Randomized experiment.
  
  
  
  Research laboratory at a university hospital.
  
  
  
  Experimental severe acute pancreatitis in rats.
  
  
  
  Severe acute pancreatitis was induced by retrograde injection of sodium taurocholate (50 mg/kg) into the biliopancreatic duct. In dose-study, rats were administered with different doses of tocilizumab (1, 2, 4, 8, and 16 mg/kg) through the tail vein after severe acute pancreatitis induction. In safety-study, rats without severe acute pancreatitis induction were treated with high doses of tocilizumab (8, 16, 32, and 64 mg/kg). Serum and tissue samples of rats in time-study were collected for biomolecular and histologic evaluations at different time points (2, 6, 12, 18, and 24 hr).
  
  
  
  1) Under the administration of tocilizumab, histopathological scores of pancreas and lung were decreased, and severity parameters related to severe acute pancreatitis and associated lung injury, including serum amylase, C-reactive protein, lung surfactant protein level, and myeloperoxidase activity, were all significant alleviated in rat models. 2) Dose-study demonstrated that 2 mg/kg tocilizumab was the optimal treatment dose. 3) Basing on multi-organ pathologic evaluation, physiological and biochemical data, no adverse effect and toxicity of tocilizumab were observed in safety-study. 4) Pancreatic nuclear factor-κB and signal transducer and activator of transcription 3 were deactivated, and the serum chemokine (C-X-C motif) ligand 1 was down-regulated after tocilizumab administration.
  
  
  
  Our study demonstrated tocilizumab, as a marketed drug commonly used for immune-mediated diseases, was safe and effective for the treatment of experimental severe acute pancreatitis and associated acute lung injury. Our findings provide experimental evidences for potential clinical application of tocilizumab in severe acute pancreatitis and associated complications.
authors.affiliation: 1Institute of Digestive Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China. 2Department of Gastroenterological Surgery, West China Hospital, Sichuan University, Chengdu, China. 3Department of Oncology, Department of Clinical and Experiment Medicine, Linköping University, Linköping, Sweden. 4Department of General Surgery, Shanghai First People's Hospital, Shanghai Jiaotong University, Shanghai, China.
authors.forename: Ke-Ling
authors.initials: KL
authors.lastname: Chen
authors.forename: Zhao-Ying
authors.initials: ZY
authors.lastname: Lv
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Yang
authors.forename: Yong
authors.initials: Y
authors.lastname: Liu
authors.forename: Fei-Wu
authors.initials: FW
authors.lastname: Long
authors.forename: Bin
authors.initials: B
authors.lastname: Zhou
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Sun
authors.forename: Zhi-Hai
authors.initials: ZH
authors.lastname: Peng
authors.forename: Zong-Guang
authors.initials: ZG
authors.lastname: Zhou
authors.forename: Yuan
authors.initials: Y
authors.lastname: Li
mesh_terms: D000208:Acute Disease; D055371:Acute Lung Injury / Q000188:drug therapy*; D000681:Amylases / Q000378:metabolism; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002097:C-Reactive Protein / Q000378:metabolism; D054360:Chemokine CXCL1 / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015850:Interleukin-6 / Q000378:metabolism*; D016328:NF-kappa B / Q000096:biosynthesis; D010195:Pancreatitis / Q000188:drug therapy*; D009195:Peroxidase / Q000378:metabolism; D037661:Pulmonary Surfactant-Associated Proteins / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects; D014157:Transcription Factors / Q000187:drug effects
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D054360:Chemokine CXCL1; C508600:IL6 protein, human; D015850:Interleukin-6; D016328:NF-kappa B; D037661:Pulmonary Surfactant-Associated Proteins; D014157:Transcription Factors; D002097:C-Reactive Protein; D009195:Peroxidase; D000681:Amylases; C502936:tocilizumab