heparitin-sulfate and Pancreatitis

Malfunctioning of the intestinal microcirculation secondary to severe acute pancreatitis (SAP) can cause injuries to the intestinal mucosal barrier, translocation of gut flora, and sepsis. The glycocalyx on the vascular endothelium helps maintain its normal function through multiple mechanisms, including regulation of vascular permeability and inhibition of intercellular adhesion. It is unknown that whether pancreatitis inflicts injuries to the intestinal mucosal barrier through damaging glycocalyx or stabilizing glycocalyx can be a potential therapeutic target in maintaining the integrity of the intestinal mucosal barrier during SAP. Injecting sodium taurocholate into the pancreatic duct of Sprague-Dawley rats induced SAP. Intestinal perfusion, changes in endothelial glycocalyx, and the associated molecular mechanisms were assessed by laser Doppler velocimetry, electron microscopy, and the levels of heparan sulfate, syndacan-1, and tumor necrosis factor-α (TNF-α) in the superior mesenteric vein. Protective effects of hydrocortisone treatment in the intestinal microcirculation during SAP were evaluated. Degradation of the glycocalyx in intestinal vascular endothelium developed 3 h after the onset of SAP in rats. By 12 h, significant reduction of intestinal perfusion was observed. The concomitant elevated levels of TNF-α in the superior mesenteric vein suggest that TNF-α is involved in the degradation of the glycocalyx. With the use of hydrocortisone, intestinal perfusion was improved and the degradation of glycocalyx was reduced. The degradation of glycocalyx is involved in the malfunction of the intestinal microcirculation. The massive release of TNF-α participates in this process and leads to glycocalyx degradation. Hydrocortisone may be a good therapy to prevent this process.

Topics: Animals; Cell Adhesion; Disease Models, Animal; Endothelium, Vascular; Glycocalyx; Heparitin Sulfate; Hydrocortisone; Intestines; Male; Mesenteric Veins; Microcirculation; Pancreatitis; Perfusion; Permeability; Rats; Rats, Sprague-Dawley; Sepsis; Syndecan-1; Taurocholic Acid; Time Factors; Tumor Necrosis Factor-alpha

In severe acute pancreatitis, the administration of fluids in the presence of positive fluid responsiveness is associated with better outcome when compared to guiding therapy on central venous pressure. We compared the effects of such consequent maximization of stroke volume index with a regime using individual values of stroke volume index assessed prior to severe acute pancreatitis induction as therapeutic hemodynamic goals.. Prospective, randomized animal study.. University animal research laboratory.. Thirty domestic pigs.. After randomization, fluid resuscitation was started 2 hours after severe acute pancreatitis induction and continued for 6 hours according to the respective treatment algorithms. In the control group, fluid therapy was directed by maximizing stroke volume index, and in the study group, stroke volume index assessed prior to severe acute pancreatitis served as primary hemodynamic goal.. Within the first 6 hours of severe acute pancreatitis, the study group received a total of 1,935.8 ± 540.7 mL of fluids compared with 3,462.8 ± 828.2 mL in the control group (p < 0.001). Pancreatic tissue oxygenation did not differ significantly between both groups. Vascular endothelial function, measured by flow-mediated vasodilation before and 6 hours after severe acute pancreatitis induction, revealed less impairment in the study group after treatment interval (-90.76% [study group] vs -130.89% [control group]; p = 0.046). Further, lower levels of heparan sulfate (3.41 ± 5.6 pg/mL [study group] vs 43.67 ± 46.61 pg/mL [control group]; p = 0.032) and interleukin 6 (32.18 ± 8.81 pg/mL [study group] vs 77.76 ± 56.86 pg/mL [control group]; p = 0.021) were found in the study group compared with control group. Histopathological examination of the pancreatic head and corpus at day 7 revealed less edema for the study group compared with the control group (1.82 ± 0.87 [study group] vs 2.89 ± 0.33 [control group, pancreatic head]; p = 0.03; 2.2 ± 0.92 [study group] vs 2.91 ± 0.3 [control group, pancreatic corpus]; p = 0.025).. Individualized optimization of intravascular fluid status during the early course of severe acute pancreatitis, compared with a treatment strategy of maximizing stroke volume by fluid loading, leads to less vascular endothelial damage, pancreatic edema, and inflammatory response.

Topics: Acute Disease; Animals; Disease Models, Animal; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fluid Therapy; Glycocalyx; Hemodynamics; Heparitin Sulfate; Inflammation; Pancreatitis; Prospective Studies; Random Allocation; Severity of Illness Index; Stroke Volume; Swine; Syndecan-1

Systemic inflammatory mediators, including the protein high-mobility group box 1 (HMGB1), play an important role in the development of acute pancreatitis. Anticoagulants such as danaparoid sodium (DA) may be able to inhibit sepsis-induced inflammation, but the mechanism of action is not well understood. We hypothesized that DA would act as an inhibitor of inflammation and prevent cerulein-induced acute pancreatitis. Male Wistar rats were used as subjects in this study. Each received a bolus of 50 U/kg of DA or saline-injected into the tail vein, followed by 4 injections of 50 mg/kg cerulean (i.p.) at 1-h intervals. Cytokine (IL-6), NO, and HMGB1 levels in serum and pancreatic tissue were measured after the cerulein injection. Pancreas histopathology and wet-dry ratio significantly improved in the DA-injected (50 U/kg) animals compared with saline-injected rats. Serum and pancreatic HMGB1 levels decreased over time in DA-treated animals. Danaparoid sodium also decreased cytokine, NO, and HMGB1 levels during cerulein-induced inflammation. As a result, DA ameliorated pancreas pathology in the rat model of cerulein-induced acute pancreatitis. This study demonstrates that DA treatment prevents cerulein-induced acute pancreatitis in a rat model. This effect may be mediated through inhibition of cytokines, NO, and HMGB1.

Topics: Animals; Blotting, Western; Ceruletide; Chondroitin Sulfates; Dermatan Sulfate; Fibrinolytic Agents; Heparitin Sulfate; HMGB1 Protein; Immunohistochemistry; Interleukin-6; Male; NF-kappa B; Nitrates; Nitric Oxide Synthase Type II; Nitrites; Pancreas; Pancreatitis; Peroxidase; Rats

The initiating events in the onset of pancreatitis are poorly understood. Possible candidates may be endogenous ligands, acting on receptors within ductal, acinar or stellate cells, which have previously been shown to cause a systemic inflammatory response syndrome. The aim of this study was to investigate whether acute pancreatitis could be induced by heparan sulphate (HS)infused into the pancreatic ducts in the rat.. Retrograde biliary-pancreatic infusion of heparan sulphate of different structures, taurodeoxycholate (TDC) or phosphate buffered saline (PBS) was performed. Local pancreatic inflammation was evaluated after 6 h by means of morphological evaluation, neutrophil and macrophage infiltration and levels of plasma amylase. Systemic inflammation was evaluated by measuring plasma IL-6, MCP-1 and CINC-1 concentrations.. Heparan sulphate induced a local inflammatory response visualized as a rapid infiltration of neutrophils and macrophages into the pancreas. Heparan sulphate induced inflammation and oedema without causing damage to acinar cells, as measured by morphological changes and plasma amylase concentrations. Furthermore, an increase in serum concentrations of CINC-1 and IL-6 was seen. The positive control (TDC) had increased levels of all variables analysed and the negative control (heparan sulphate administered intraperitoneally) was without effects.. Our findings suggest a receptor-mediated innate immune response of the pancreatic cells induced by heparan sulphate. This finding may be helpful in elucidating some of the mechanisms involved during the initiation of pancreatitis, as well as in the search for a potential future therapeutic application.

Topics: Acute Disease; Animals; Chemokine CCL2; Chemokine CXCL1; Heparitin Sulfate; Interleukin-6; Male; Pancreas; Pancreatitis; Peroxidase; Rats; Rats, Sprague-Dawley; Taurodeoxycholic Acid