Original Article
Copyright ©2013 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Nov 7, 2013; 19(41): 7097-7105
Published online Nov 7, 2013. doi: 10.3748/wjg.v19.i41.7097
C/EBP homologous protein deficiency aggravates acute pancreatitis and associated lung injury
Te-I Weng, Hsiao-Yi Wu, Bo-Lin Chen, Jie-Yang Jhuang, Kuo-How Huang, Chih-Kang Chiang, Shing-Hwa Liu
Te-I Weng, Hsiao-Yi Wu, Department of Forensic Medicine, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Te-I Weng, Department of Emergency Medicine, National Taiwan University Hospital, Taipei 100, Taiwan
Bo-Lin Chen, Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Jie-Yang Jhuang, Department of Pathology, Far Eastern Memorial Hospital, Taipei 220, Taiwan
Kuo-How Huang, Department of Urology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
Chih-Kang Chiang, Departments of Integrated Diagnostics and Therapeutics and Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan
Shing-Hwa Liu, Institute of Toxicology, College of Medicine, and Department of Pediatrics, National Taiwan University Hospital and College of Medicine, Taipei 100, Taiwan
Author contributions: Weng TI and Liu SH contributed equally to this work; Weng TI and Chiang CK prepared the testing samples and analyzed the research data and wrote the manuscript; Wu HY, Chen BL, Jhuang JY and Huang KH collected/analyzed the research data and contributed to discussion; Liu SH designed the experiments and wrote/reviewed/edited the manuscript.
Supported by A research grant from the National Science Council of Taiwan, No. NSC97-2320-B-002-020-MY3
Correspondence to: Shing-Hwa Liu, PhD, Professor, Institute of Toxicology, College of Medicine, National Taiwan University, No. 1, Jen-Ai Road, Section 1, Taipei 100, Taiwan. shinghwaliu@ntu.edu.tw
Telephone: +886-2-23123456-88605 Fax: +886-2-23410217
Received: May 9, 2013
Revised: July 27, 2013
Accepted: August 17, 2013
Published online: November 7, 2013
Processing time: 192 Days and 5.8 Hours
Abstract

AIM: To investigate the pathophysiological role of C/EBP homologous protein (CHOP) in severe acute pancreatitis and associated lung injury.

METHODS: A severe acute pancreatitis model was induced with 6 injections of cerulein (Cn, 50 μg/kg) at 1-h intervals, then intraperitoneal injection of lipopolysaccharide (LPS, 7.5 mg/kg) in CHOP-deficient (Chop-/-) mice and wild-type (WT) mice. Animals were sacrificed under anesthesia, 3 h or 18 h after LPS injection. Serum amylase, lipase, and cytokines [interleukin (IL)-6 and tumor necrosis factor (TNF)-α], pathological changes, acute lung injury, and apoptosis in the pancreas were evaluated. Serum amylase and lipase activities were detected using a medical automatic chemical analyzer. Enzyme-linked immunosorbent assay kits were used to evaluate TNF-α and IL-6 levels in mouse serum and lung tissue homogenates. Apoptotic cells in sections of pancreatic tissues were determined by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling (TUNEL) analysis. The mouse carotid arteries were cannulated and arterial blood samples were collected for PaO2 analysis. The oxygenation index was expressed as PaO2/FiO2.

RESULTS: Administration of Cn and LPS for 9 and 24 h induced severe acute pancreatitis in Chop-/- and WT mice. When comparing Chop-/- mice and WT mice, we observed that CHOP-deficient mice had greater increases in serum TNF-α (214.40 ± 19.52 pg/mL vs 150.40 ± 16.70 pg/mL; P = 0.037), amylase (4236.40 ± 646.32 U/L vs 2535.30 ± 81.83 U/L; P = 0.041), lipase (1678.20 ± 170.57 U/L vs 1046.21 ± 35.37 U/L; P = 0.008), and IL-6 (2054.44 ± 293.81 pg/mL vs 1316.10 ± 108.74 pg/mL; P = 0.046) than WT mice. The histopathological changes in the pancreases and lungs, decreased PaO2/FiO2 ratio, and increased TNF-α and IL-6 levels in the lungs were greater in Chop-/- mice than in WT mice (pancreas: Chop-/-vs WT mice, hemorrhage, P = 0.005; edema, P = 0.005; inflammatory cells infiltration, P = 0.005; total scores, P = 0.006; lung: hemorrhage, P = 0.017; edema, P = 0.017; congestion, P = 0.017; neutrophil infiltration, P = 0.005, total scores, P = 0.001; PaO2/FiO2 ratio: 393 ± 17.65 vs 453.8, P = 0.041; TNF-α: P = 0.043; IL-6, P = 0.040). Results from TUNEL analysis indicated increased acinar cell apoptosis in mice following the induction of acute pancreatitis. However, Chop-/- mice displayed significantly reduced pancreatic apoptosis compared with the WT mice (201.50 ± 31.43 vs 367.00 ± 47.88, P = 0.016).

CONCLUSION: These results suggest that CHOP can exert protective effects against acute pancreatitis and limit the spread of inflammatory damage to the lungs.

Keywords: C/EBP homologous protein; Acute pancreatitis, Lung injury; Cytokines; Apoptosis

Core tip: We found that mice lacking C/EBP homologous protein (CHOP) had aggravated acute pancreatitis-induced increases in the severity of pancreatic pathology, pancreatitis-associated lung injury, and cytokines interleukin-6 and tumor necrosis factor-α levels compared with wild-type (WT) mice. Pancreatic apoptosis was also lower in Chop-/- mice than in WT mice during acute pancreatitis. These results suggest that CHOP exerts protective effects against acute pancreatitis and limits the spread of inflammatory damage to the lungs.