Acute pancreatitis in obesity: adipokines and dietary fish oil.

BACKGROUND: Acute pancreatitis is a substantial clinical problem accounting for 240,000 hospital admissions yearly in the United States. Obesity is epidemic and is clearly an independent risk factor for increased severity of acute pancreatitis (AP). Adipose tissue is an endocrine organ that secretes a variety of metabolically active substances termed adipokines. However, the role of adipokines in modulating acute pancreatitis severity remains incompletely understood. Dietary fish oil is rich in omega-3 free fatty acids and attenuates adipose tissue-induced inflammation. Therefore, we hypothesized that feeding obese mice diets rich in fish oil would alter the adipokine milieu and attenuate the severity of pancreatitis. METHODS: Lean (C57BL/6 J) and obese (LepDb) mice were fed either a soybean oil- or fish oil-rich diet for 4 weeks. AP was induced by six hourly intraperitoneal injections of cerulein (50 µg/kg). Serum adipokine levels were measured, and pancreatitis severity was assessed histologically and by measuring pancreatic concentrations of interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), myleoperoxidase (MPO), and monocyte chemoattractant protein-1 (MCP-1). RESULTS: Obese mice developed more severe pancreatitis than lean mice. Fish oil significantly decreased serum leptin (lean and obese) and increased serum adiponectin (lean only). Fish oil did not alter the baseline pancreatic inflammatory milieu, nor did it change histologic or biochemical pancreatitis severity. CONCLUSION: These data demonstrate that a diet rich in fish oil altered the adipokine milieu in lean and congenitally obese mice; however, fish oil did not improve pancreatitis severity induced with cerulein hyperstimulation.

Adipokines and cytokines in human pancreatic juice: unraveling the local pancreatic inflammatory milieu.

BACKGROUND: Differential adipokine expression in obesity influences the inflammatory milieu, and may explain in part obesity's negative impact on pancreatic disease. Pancreatic juice analysis may provide a good means to evaluate the local pancreatic inflammatory milieu. The presence of adipokines in pancreatic juice is unknown. AIMS: This proof-of-concept study was designed to determine the presence of adipokines and cytokines in human pancreatic juice. METHODS: With institutional review board approval, pancreatic juice was obtained from ten patients with a broad range of diagnoses at the time of endoscopic retrograde cholangiopancreatography. Pancreatic juice was assayed using enzyme-linked immunosorbent assay (ELISA) for insulin, the proinflammatory adipokine leptin, the anti-inflammatory adipokine adiponectin, and the inflammatory mediators interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and monocyte chemoattractant protein-1 (MCP-1). Correlation between adipokine and inflammatory mediator expression was determined by linear regression analysis. Data are presented as mean +/- standard error of the mean (SEM); P < 0.05 was considered statistically significant. RESULTS: Leptin (0.16 +/- 0.05 ng/ml) and adiponectin (0.63 +/- 0.02 microg/ml) were both present, as were the inflammatory mediators IL-6 (112.6 +/- 28.1 pg/ml), TNF-alpha (49.0 +/- 18.8 pg/ml), and MCP-1 (32.2 +/- 0.9 pg/ml). Paradoxically, the expression of the anti-inflammatory adipokine adiponectin correlated strongly with that of the proinflammatory cytokine IL-6 (R(2) = 0.98, P < 0.001). CONCLUSIONS: This report is the first to describe adipokine expression in human pancreatic juice. Human pancreatic juice inflammatory mediators and adipokines may provide an important measurement of the local pancreatic inflammatory milieu.

Nuclear magnetic resonance spectroscopy-based metabolomics of the fatty pancreas: implicating fat in pancreatic pathology.

BACKGROUND: Obesity is a worldwide epidemic and a significant risk factor for pancreatic diseases including pancreatitis and pancreatic cancer; the mechanisms underlying this association are unknown. Metabolomics is a powerful new analytical approach for describing the metabolome (compliment of small molecules) of cells, tissue or biofluids at any given time. Our aim was to analyze pancreatic fat content in lean and congenitally obese mice using both metabolomic analysis and conventional chromatography. METHODS: The pancreatic fat content of 12 lean (C57BL/6J), 12 obese leptin-deficient (Lep(ob)) and 12 obese hyperleptinemic (Lep(db)) mice was evaluated by metabolomic analysis, thin-layer and gas chromatography. RESULTS: Pancreata of congenitally obese mice had significantly more total pancreatic fat, triglycerides and free fatty acids, but significantly less phospholipids and cholesterol than those of lean mice. Metabolomic analysis showed excellent correlation with thin-layer and gas chromatography in measuring total fat, triglycerides and phospholipids. CONCLUSIONS: Differences in pancreatic fat content and character may have important implications when considering the local pancreatic proinflammatory milieu in obesity. Metabolomic analysis is a valid, powerful tool with which to further define the mechanisms by which fat impacts pancreatic disease.

Adiponectin receptor-1 expression is decreased in the pancreas of obese mice.

BACKGROUND: Obesity is epidemic in the 21st century and has been shown to be a risk factor for developing severe acute pancreatitis. Adipose tissue produces small molecules called adipokines, which are important in modulating metabolism and inflammation. The anti-inflammatory adipokine adiponectin is decreased in obesity and inversely mirrors the severity of pancreatitis in a murine experimental model. Adiponectin acts through two receptors, AdipoR1 and AdipoR2; no data are currently available regarding adiponection receptor expression in the obese murine pancreas. MATERIALS AND METHODS: Immunohistochemical and reverse transcription-polymerase chain reaction analysis were undertaken to determine expression of adiponectin receptors AdipoR1 and AdipoR2 in the pancreas and liver of lean (C57BL/6J) and congenitally obese (Lep(Ob) and Lep(Db)) mice. RESULTS: Immunohistochemistry confirmed expression of both AdipoR1 and AdipoR2 in the pancreas of all three murine strains. Staining was positive in acinar cells and to a lesser extent in islet cells. Pancreatic gene expression of AdipoR2 was similar among lean and obese mice. AdipoR1 gene expression, however, was significantly (P < 0.001) decreased in the pancreas of both Lep(Ob) and Lep(Db) mice compared to wild-type lean animals. Gene expression of both AdipoR1 and AdipoR2 was significantly less in the liver of obese (Lep(Ob) and Lep(Db)) mice compared to wild-type lean animals (P < 0.001). CONCLUSIONS: These data show for the first time that the adiponectin receptors AdipoR1 and AdipoR2 are expressed in the obese murine pancreas. The paucity of AdipoR1 receptors may be important when considering the role played by adipokines in the genesis of severe pancreatitis in obesity.

Validation of a novel, physiologic model of experimental acute pancreatitis in the mouse.

BACKGROUND: Many experimental models of acute pancreatitis suffer from lack of clinical relevance. We sought to validate a recently reported murine model of acute pancreatitis that more closely represents the physiology of human biliary pancreatitis. METHODS: Mice (C57BL/6J n=6 and CF-1 n=8) underwent infusion of 50µl of 5% sodium taurocholate (NaT) or 50µl of normal saline (NaCl) directly into the pancreatic duct. Twenty-four hours later, pancreatitis severity was graded histologically by three independent observers, and pancreatic tissue concentration of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) were determined by ELISA. RESULTS: Twenty four hours after retrograde injection, the total pancreatitis score was significantly greater in mice infused with NaT than in those infused with NaCl (6.3 ± 1.2 vs. 1.2 ± 0.4, p<0.05). In addition, the inflammatory mediators IL-6 and MCP-1 were increased in the NaT group relative to the NaCl group. DISCUSSION: Retrograde pancreatic duct infusion of sodium taurocholate induces acute pancreatitis in the mouse. This model is likely representative of human biliary pancreatitis pathophysiology, and therefore provides a powerful tool with which to elucidate basic mechanisms underlying the pathogenesis of acute pancreatitis.

Cannabinoid receptor-1 blockade attenuates acute pancreatitis in obesity by an adiponectin mediated mechanism.

BACKGROUND: Obesity is a risk factor for increased severity of acute pancreatitis. Adipocytes produce adiponectin, an anti-inflammatory molecule that is paradoxically decreased in the setting of obesity. We have shown that adiponectin concentration inversely mirrors the severity of pancreatitis in obese mice. Cannabinoid receptor CB-1 blockade increases circulating adiponectin concentration. We, therefore, hypothesize that blockade of CB-1 would increase adiponectin and attenuate pancreatitis severity. METHODS: Forty lean (C57BL/6J) and 40 obese (Lep(Db)) mice were studied. Half of the mice in each strain received intraperitoneal injection of the CB-1 antagonist rimonabant (10 mg/kg daily for 7 days); the others received vehicle. Pancreatitis was induced by intraperitoneal injection of cerulein (50 microg/g hourly x 6). Pancreatitis severity was determined by histology. Pancreatic chemokine and proinflammatory cytokine concentrations were measured by ELISA. RESULTS: Rimonabant treatment significantly increased circulating adiponectin concentration in obese mice (p < 0.03 vs. vehicle). After induction of pancreatitis, obese mice treated with rimonabant had significantly decreased histologic pancreatitis (p < 0.001), significantly lower pancreatic tissue levels of monocyte chemoattractant protein-1 (p = 0.03), tumor necrosis factor-alpha (p < 0.001), interleukin-6 (p < 0.001), and myeloperoxidase (p = 0.006) relative to vehicle-treated animals. CONCLUSIONS: In obese mice, cannabinoid receptor CB-1 blockade with rimonabant attenuates the severity of acute pancreatitis by an adiponectin-mediated mechanism.

A murine model of obesity implicates the adipokine milieu in the pathogenesis of severe acute pancreatitis.

Obesity is clearly an independent risk factor for increased severity of acute pancreatitis (AP), although the mechanisms underlying this association are unknown. Adipokines (including leptin and adiponectin) are pleiotropic molecules produced by adipocytes that are important regulators of the inflammatory response. We hypothesized that the altered adipokine milieu observed in obesity contributes to the increased severity of pancreatitis. Lean (C57BL/6J), obese leptin-deficient (LepOb), and obese hyperleptinemic (LepDb) mice were subjected to AP by six hourly intraperitoneal injections of cerulein (50 microg/kg). Severity of AP was assessed by histology and by measuring pancreatic concentration of the proinflammatory cytokines IL-1beta and IL-6, the chemokine MCP-1, and the marker of neutrophil activation MPO. Both congenitally obese strains of mice developed significantly more severe AP than wild-type lean animals. Severity of AP was not solely related to adipose tissue volume: LepOb mice were heaviest; however, LepDb mice developed the most severe AP both histologically and biochemically. Circulating adiponectin concentrations inversely mirrored the severity of pancreatitis. These data demonstrate that congenitally obese mice develop more severe AP than lean animals when challenged by cerulein hyperstimulation and suggest that alteration of the adipokine milieu exacerbates the severity of AP in obesity.

Ventilator-associated pneumonia after combined burn and trauma is caused by associated injuries and not the burn wound.

An increased risk of ventilator-associated pneumonia (VAP) has previously been demonstrated in trauma patients urgently intubated in the prehospital (ie, field) and emergency department (ED) settings. This study investigated the impact of urgent intubation on subsequent VAP in patients who sustained both a burn injury and a traumatic injury. We undertook a retrospective review of both trauma registry data and medical records for all patients with combined thermal and traumatic injuries admitted to a single verified burn center and level I trauma center. Patients undergoing field or ED intubation during the 5-year period ending December 2002 were identified and studied. Data abstracted included admission demographics and vital signs, presence of inhalation injury, location at the time of intubation, presence of associated injury, percentage TBSA burn, hospital and intensive care unit length of stay, and hospital day of VAP diagnosis. Seventy-eight of the 3388 patients (2.3%) admitted during the study period sustained a combination of burn wounds and trauma and underwent urgent field or ED intubation. The majority of patients were men (71%), with a mean age of 46 +/- 24 years. There was one failed oral intubation, which required cricothyroidotomy. The location of the patient at the time of intubation was ED, 66%; burn center ED, 17%; and field, 17%. Eighty percent of all patients were diagnosed with an inhalation injury. VAP was diagnosed in 39 patients (50%), with a mean time to diagnosis of 10 +/- 9 days. TBSA burn, smoke inhalation, and time (in days) to diagnosis of VAP were not independent risk factors for the occurrence of pneumonia in any of the 3 groups. However, those intubated at the initial ED were more likely to develop VAP (P = .028) compared to those intubated in the field or in the burn center. The incidence of associated injuries was significantly greater (P < .0001) in the initial ED group. Only a small percentage of burn patients also sustain blunt trauma. VAP occurs in 50% of the patients requiring urgent intubation. Independent risk factors appear to be intubation at an initial ED before transfer and associated injuries.