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Effects of Tocilizumab on Experimental Severe Acute Pancreatitis and Associated Acute Lung Injury.
- Source :
-
Critical care medicine [Crit Care Med] 2016 Aug; Vol. 44 (8), pp. e664-77. - Publication Year :
- 2016
-
Abstract
- Objective: 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.<br />Design: Randomized experiment.<br />Setting: Research laboratory at a university hospital.<br />Subject: Experimental severe acute pancreatitis in rats.<br />Interventions: 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).<br />Measurements and Main Results: 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.<br />Conclusions: 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.
- Subjects :
- Acute Disease
Amylases metabolism
Animals
Antibodies, Monoclonal, Humanized administration & dosage
Antibodies, Monoclonal, Humanized adverse effects
C-Reactive Protein metabolism
Chemokine CXCL1 drug effects
Disease Models, Animal
Dose-Response Relationship, Drug
NF-kappa B biosynthesis
Peroxidase metabolism
Pulmonary Surfactant-Associated Proteins metabolism
Random Allocation
Rats
Severity of Illness Index
Signal Transduction drug effects
Transcription Factors drug effects
Acute Lung Injury drug therapy
Antibodies, Monoclonal, Humanized pharmacology
Interleukin-6 metabolism
Pancreatitis drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0293
- Volume :
- 44
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- Critical care medicine
- Publication Type :
- Academic Journal
- Accession number :
- 26963319
- Full Text :
- https://doi.org/10.1097/CCM.0000000000001639