C/EBP homologous protein deficiency aggravates acute pancreatitis and associated lung injury

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 mu g/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)-alpha], 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-alpha 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/FiO(2). 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-alpha (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/FiO(2) ratio, and increased TNF-alpha 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/FiO(2) ratio: 393 +/- 17.65 vs 453.8, P = 0.041; TNF-alpha: P = 0.043; IL-6, P = 0.040). Results from TU-NEL 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. (C) 2013 Baishideng Publishing Group Co., Limited. All rights reserved