Melatonin reduces pancreatic prostaglandins production and protects against caerulein-induced pancreatitis in rats.

Melatonin has been used to treat experimental pancreatitis, although not all the drug's therapeutic mechanisms of melatonin have been defined. Prostaglandins (PGs) are proinflammatory mediators that exert their effects mainly locally during inflammatory diseases. The present study was undertaken to examine whether treatment with melatonin influences local PG production. An acute pancreatitis model in male Sprague-Dawley rats (225-275 g) was established by continuously infusing caerulein (15 mg/kg/hr). Mean arterial pressure and pancreatic perfusion were monitored continuously. Melatonin was delivered via the intraperitoneal route at doses of either 2 or 10 mg/kg, 30 min after caerulein injection. Malondialdehyde and glutathione levels of the pancreas and liver and the trypsinogen activation peptide levels in the serum were measured at the end of the experiment (8 hr after infusion of caerulein). Intraperitoneal injection of melatonin (2 and 10 mg/kg) reduced the reduction in systemic arterial pressure and decreased pancreatic perfusion in the rat model of caerulein pancreatitis. Moreover, melatonin treatment changed local PG production toward control level. Higher dose of melatonin was somewhat more effective in preventing the caerulein-induced alterations than was the lower dose.

Delayed neutrophil apoptosis attenuated by melatonin in human acute pancreatitis.

OBJECTIVES: This study evaluated the expression of neutrophil apoptosis and the effects of melatonin at different concentrations on delayed neutrophil apoptosis in different severities of acute pancreatitis in patients. METHODS: The study population was comprised of 10 patients with severe acute pancreatitis (SAP) and 10 with mild acute pancreatitis (MAP). A total of 10 mL of blood was drawn 24 hours after the onset of the clinical disease for isolation and incubation of the human neutrophils with 4 different concentrations of melatonin. Neutrophil apoptosis activity, CD18 expression, and respiratory burst activity were assessed with flow cytometry 12 hours after incubation. Another group of neutrophils from a healthy control group was used (n = 6) for comparison. RESULTS: Neutrophil apoptosis in patients with SAP is delayed compared with that of patients with MAP. Neutrophils from patients with SAP or MAP are functionally activated. Melatonin at concentrations of 10(-8), 10(-7), or 10(-6) M reverses the delayed process and enhances apoptosis activity in neutrophils in patients with MAP. Melatonin at concentrations of 10(-7) and 10(-6) M reverses the delayed process and increases apoptosis activity in neutrophils in patients with SAP. Neutrophils from patients with SAP and MAP showed significantly increased CD18 expression and respiratory burst activity. Melatonin at concentrations of 10(-7) or 10(-6) M reverses CD18 expression and respiratory burst activity in neutrophils in patients with SAP. CONCLUSIONS: This study highlights the importance of neutrophil apoptosis in patients with SAP and raises the possibility of a therapeutic strategy. Study data show that melatonin promotes neutrophil apoptosis in human acute pancreatitis.

Efficacy of gabexate mesilate on disseminated intravascular coagulation as a complication of infection developing after abdominal surgery.

BACKGROUND AND PURPOSE: Gabexate mesilate (GM) is a promising anticoagulation treatment for disseminated intravascular coagulation (DIC). This study was designed to examine the effect of GM on DIC associated with the development of infection after abdominal surgery in the intensive care unit (ICU). METHODS: From January 1999 to March 2002, 50 consecutive ICU patients suffering DIC associated with the development of infection after abdominal surgery were enrolled in this study. Twenty five of the patients were randomized to receive treatment with GM by central intravenous infusion at 1 mg/kg/hour for 5 days or longer, while the remaining 25 were not treated. Blood clotting tests were performed and cytokine levels including tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were examined on days 1, 3, and 7 after admission. General blood tests and D-dimer tests were conducted before and after GM administration. The gender, age, mortality, Acute Physiology and Chronic Health Evaluation II (APACHE-II) scores and severity of DIC were compared between the 2 groups. RESULTS: No significant difference was found between the 2 groups in TNF-alpha and IL-6 concentration on days 1, 3, and 7. The mortality rate was similar between the 2 groups. However, DIC and APACHE-II scores were significantly lower in the GM-treated patients than in controls. CONCLUSION: In this study, GM (1 mg/kg/hour) did not reduce the concentration of TNF-alpha and IL-6, or alter the mortality rate in patients with DIC resulting from infectious complications after surgery. Nevertheless, APACHE-II scores indicated that GM reduced the DIC severity and improved the clinical condition of patients.

Results of treating severe acute pancreatitis with gabexate is associated with neutrophil apoptosis activity.

BACKGROUND/AIMS: A delay in polymorphonuclear neutrophil apoptosis has been implicated in the pathogenesis of systemic inflammatory reactions in certain conditions. Gabexate mesilate has been proven effective in the treatment of severe acute pancreatitis with organ dysfunction. In this study, we attempted to answer the questions of whether neutrophil apoptosis is associated with the conditions of various major organs in patients with severe acute pancreatitis and receiving gabexate. METHODOLOGY: A total of 45 patients were included in this study. We divide the patients into two groups. Group A included patients with > or = 2 complications after one-week treatment (n = 31), and Group B included patients with < 2 complications after one-week treatment (n = 14). Serum interleukin-6 and interleukin-8 was detected at day 1, 3, and 7 of treatment using enzyme-linked immunosorbent assay kits. The neutrophil CD18 expression and apoptosis activity were evaluated flowcytometrically at day 1, 3, and 7 of treatment. RESULTS: At day 7 of treatment, interleukin-6 levels were significantly higher in Group B while interleukin-8 levels were not different. The neutrophil CD18 expression was significantly higher and delayed ex vivo apoptosis was significantly lower in the group B than that of group A at day 7 of treatment. CONCLUSIONS: In patients of severe acute pancreatitis with organ dysfunction and receiving gabexate treatment, neutrophil apoptosis is associated with the severity of organ dysfunction.

Beneficial role of melatonin on microcirculation in endotoxin-induced gastropathy in rats: possible implication in nitrogen oxide reduction.

BACKGROUND AND PURPOSE: Lipopolysaccharide (LPS) induces hemodynamic changes and microcirculatory derangement in various organs. Melatonin may exert a beneficial effect on gastric tissue in LPS-induced gastropathy. However, the role of nitric oxide (NO) has not been clarified. MATERIALS AND METHODS: Adult male Sprague-Dawley rats were divided into three groups: control, n = 9; LPS (intraperitoneal LPS, 50 mg/kg), n = 9; and LPS + M (LPS, 50 mg/kg; intragastric melatonin 20 mg/kg), n = 9. Mean arterial blood pressure (MAP) was monitored throughout the experiment (8 h). In vivo microscopy was used to investigate gastric microcirculation, including flow velocity and leukocyte adhesion. Tissue malondialdehyde (MDA) and gastric aspirate parameters (protein content, glucose content, volume) were determined as the gastric damage index at the end of the experiment. Microdialysis was used to measure the sum of nitrite and nitrate concentrations. RESULTS: Compared with LPS alone, LPS with melatonin significantly improved gastric microcirculation but not systemic hemodynamics. LPS-induced gastropathy was quantified according to the increased adherent leukocyte count, decreased flow velocity in postcapillary venules, and increased tissue MDA production. Luminal glucose and protein content, the gastric mucosa injury index, were significantly increased. Intragastric melatonin improved microcirculatory and mucosa injury parameters. These effects of melatonin are directly associated with the tissue levels of NO products, which are increased with LPS only and much decreased with LPS and melatonin. CONCLUSIONS: This study demonstrated that melatonin contributes to the protective effects in LPS-induced gastropathy through a mechanism associated with regional production of NO.

Role of prostacyclin on microcirculation in endotoxin-induced gastroprotection in rats: a microdialysis study.

Numerous mechanisms relating to lipopolysaccharide- (LPS) induced gastroprotection have been proposed. The prostaglandin (PG) system is a promising candidate that has received considerable attention. However, the role of prostacyclin (PGI2) remains unclear. Adult, male Sprague-Dawley rats were divided into four groups: (1) control, n = 6; (2) LPS (LPS, 10 mg/kg, i.v.), n = 7; (3) LPS + indomethacin (Indo) (LPS, 10 mg/kg and indomethacin 5 mg/kg, i.v.), n = 7; and (4) Indo (indomethacin 5 mg/kg, i.v.), n = 7. Additionally, gastric microcirculation was investigated using in vivo microscopy. Tissue malondialdehyde (MDA) and glutathione levels were measured at the conclusion of the experiment. Specifically, microdialysis was used to measure the 6-keto-PGF1alpha, a stable metabolite of PGI2, while flow cytometry was used to measure the CD11b/CD18 expression of circulating neutrophils. Compared with LPS alone, LPS with Indo significantly impaired gastric microcirculation and systemic hemodynamics. LPS-induced gastroprotection was lost, as evidenced by the increased adherent leukocyte count, decreased flow velocity in the post-capillary venules, and increased tissue MDA production. Meanwhile, the luminal glucose and protein contents that comprised the gastric mucosa injury index were significantly increased. These effects of Indo are directly associated with the levels of PGI2 in gastric tissue, which increased with LPS alone and significantly decreased with a combination of LPS and Indo. This work demonstrates that PGI2 contributes to LPS-induced gastroprotection.