The current study explored the effects of intensive insulin therapy (IIT) combined with low molecular weight heparin (LMWH) anticoagulant therapy on severe acute pancreatitis (SAP). A total of 134 patients with SAP that received treatment between June 2008 and June 2012 were divided randomly into groups A (control; n=33), B (IIT; n=33), C (LMWH; n=34) and D (IIT + LMWH; n=34). Group A were treated routinely. Group B received continuous pumped insulin, as well as the routine treatment, to maintain the blood sugar level between 4.4 and 6.1 mmol/l. Group C received a subcutaneous injection of LMWH every 12 h in addition to the routine treatment. Group D received IIT + LMWH and the routine treatment. The white blood cell count, hemodiastase, serum albumin, arterial partial pressure of oxygen and prothrombin time were recorded prior to treatment and 1, 3, 5, 7 and 14 days after the initiation of treatment. The intestinal function recovery time, incidence rate of multiple organ failure (MOF), length of hospitalization and fatality rates were observed. IIT + LMWH noticeably increased the white blood cell count, hemodiastase level, serum albumin level and the arterial partial pressure of oxygen in the patients with SAP (P<0.05). It markedly shortened the intestinal recovery time and the length of stay and reduced the incidence rate of MOF, the surgery rate and the fatality rate (P<0.05). It did not aggravate the hemorrhagic tendency of SAP (P>0.05). IIT + LMWH had a noticeably improved clinical curative effect on SAP compared with that of the other treatments.
To investigate the influence of high mobility group box-1 protein (HMGB1) on the immunosuppression function of splenic regulatory T cells (Tregs) and its potential regulatory mechanism underlying the effect on CD4+ CD25- T cells in mice.CD4+ CD25+ Tregs isolated from the spleens of male BALB/c mice by magnetic beads were seeded on 96-well (1 x 10(5) cells/well) cell culture plates coated with 1 microg/ml anti-CD3 and soluble CD28. After being stimulated with HMGB1 for different time and concentrations, the secretions of IL-2 and IL-10 were analyzed by ELISA. Tregs stimulated for 72 hours were cultured with CD4+ CD25- T cells together. The suppressive activity of CD4+ CD25+ Treg to CD4+ CD25- T cells was analyzed by MTT test. IL-2, IL-10, IL-4, and interferon (IFN)-gamma in the cell suspensions were determined by ELISA.After stimulation with HMGB1, the suppressive activity of splenic Tregs in mice were significantly down-regulated at 72 hours, when the proportion of Tregs to CD4+ CD25- T cells was 1 : 1. The secretion of IL-2 of Tregs stimulated by HMGB1 was not markedly changed (P > 0.05), while a dose-dependent decrease between IL-10 induction and HMGB1 concentration was obviously (P < 0.05). When CD4+ CD25- T cells were cultured with stimulated Tregs, comparing with unstimulated-Treg group, levels of IL-2 and IFN-gamma were elevated following the increased concentration of HMGB1 (P < 0.05 or P < 0.01). Meanwhile the secretion of IL-4 and IL-10 significantly decreased when cultured with stimulated Tregs (P < 0.05).These data suggested that HMGB1 stimulation can result in significant down-regulation of immunosuppression of splenic Tregs in mice. HMGB1 might be a potential immunoregulatory signal that influences the proliferation of effector T cells, secretion of IL-2 and cells-polarization by inhibiting CD4+ CD25+ Tregs activity.
C-reactive protein (CRP) is an acute-phase protein synthesized by hepatocytes in response to pro-inflammatory cytokines and the action of interleukin-6 on the gene responsible for the transcription of CRP during inflammatory/infectious processes. CRP exists in conformationally distinct forms such as the native pentameric CRP (pCRP) and modified/monomeric CRP (mCRP) and may bind to distinct receptors and lipid rafts and exhibit different functional properties. It is known as a biomarker of acute inflammation, and many large-scale prospective studies demonstrate that CRP is both a predictor and participant in the development of cardiovascular diseases and known to be associated with chronic inflammation. In this review, we summarize and critically discuss the different functions and clinical significance of CRP in chronic inflammation and neurodegeneration. In addition, we highlight the advances in these areas that may be translated into promising measures for the diagnosis and treatment of inflammatory diseases.
To investigate the effects of escharectomy during shock stage on tissue high mobility group box-1 protein (HMGB1) expression and balance of pro-/anti-inflammatory cytokines, and to elucidate the potential mechanism underlying beneficial effect of early escharectomy after severe burns.Wistar rats inflicted by 30% full-thickness thermal injury were randomly divided into thermal injury group, 24 h escharectomy group and 72 h escharectomy group, in which escharectomy were performed at 24 and 72 h postburn, respectively. Gene expression of HMGB1, interleukin-10 (IL-10), and tumor necrosis factor-alpha (TNF-alpha) in liver and lungs was detected with reverse-transcription PCR, and protein levels of IL-10 and TNF-alpha in liver and lung tissues were measured by ELISA. The plasma AST and ALT contents, and pulmonary myeloperoxidase (MPO) activity were also assayed.The mRNA expression of HMGB1 and TNF-alpha in liver and lungs was up-regulated on postburn day 2, with IL-10 over-expression on postburn day 8. In the 24 h escharectomy group, HMGB1 and TNF-alpha mRNA expression in liver and lungs was down-regulated on postburn day 4, and IL-10 expression returned to normal range on postburn day 8, while the down-regulation of HMGB1, TNF-alpha and IL-10 were not noted in the 72 h escharectomy group. There were two peaks in liver TNF-alpha protein levels appearing on postburn days 2 and 8, respectively, with an unexpected marked decrease on day 4 in thermal injury controls, yet liver TNF-alpha levels maintained in normal range in animals of 24 h and 72 h escharectomy groups. The ratios of TNF-alpha to IL-10 protein levels in liver tissue were significantly increased on postburn days 2 and 4 (P = 0.0001 and 0.002, respectively), while escharectomy during shock stage markedly reduced hepatic TNF-alpha to IL-10 ratios (P = 0.0008 and 0.040, respectively). No significant changes in TNF-alpha protein levels in lung tissue were observed. Additionally, plasma AST as well as ALT contents, and pulmonary MPO activity were markedly decreased on postburn days 4 and 8 in the 24 h escharectomy group compared to the 72 h escharectomy group or thermal injury controls (P < 0.05).Escharectomy during burn shock stage could inhibit the over-expression of both early and late inflammatory mediators, and maintain the balance of pro-/anti-inflammatory response, thereby improving multiple organ functions in rats following severe burns.
There has been a widespread impression that tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) mediate the toxicity of high doses of lipopolysaccharide (LPS, endotoxin) and are key factors in septic shock. However, the clinical efficacy of treatment with antagonists of TNF-α and IL-1β is still controversial, suggesting that mediators other than TNF-α and IL-1β might contribute causally to endotoxin-induced death. Recent studies implicated high mobility group-1 (HMG-1) protein as a late mediator of endotoxin lethality in mice. However, the role of HMG-1 in mediating multiple organ damage-associating trauma has not been studied. This study was designed to investigate changes in HMG-1 gene expression in vital organs, and its potential role in mediating multiple organ damage following major burns. Wistar rats were subjected to a 35 percent full-thickness thermal injury, and randomly divided into three groups as follows: normal controls (n = 7), thermal injury (n = 24), and recombinant bactericidal/permeability-increasing protein (rBPI21) treatment (n = 12). Tissue samples from liver and lungs were collected to measure tissue endotoxin levels and HMG-1 mRNA expression. In addition, blood samples were obtained for measurement of organ function parameters. Our data demonstrated a significant increase in HMG-1 gene expression in tissues at 24 h postburn, which remained markedly elevated up to 72 h after thermal injury (P < 0.05–0.01). Treatment with rBPI21 could significantly decrease tissue HMG-1 mRNA expression in the liver and lung (P < 0.01). In addition, there were high positive correlations between hepatic HMG-1 mRNA and serum aminoleucine transferase (ALT) and aspartate aminotransferase (AST) levels, and also between pulmonary HMG-1 mRNA and myeloperoxidase activities (P < 0.05–0.01). Taken together, these findings indicate that thermal injury per se can markedly enhance HMG-1 gene expression in various organs. Up-regulation of HMG-1 expression may be involved in the pathogenesis of endogenous endotoxin-mediated multiple organ damage secondary to major burns.
The mechanisms of burn/trauma related infection are complicated, involving uncontrolled inflammation, immune disorder, coagulation abnormality, and pathophysiological changes of multiple systems or organs. Although active management of primary diseases, application of antibiotics, and organ support treatment are the basis for the management of burn/trauma related infection, immune modulation opens up a new direction for the intervention of burn/trauma related infection and the relevant complications. In-depth understanding of inflammation-immune response and its regulatory mechanisms, and exploring new early warning biomarkers and immune interventional strategies are of great significance for improving the level of treatment of clinical burn/trauma related infections and improving the prognosis of patients.
To explore whether extracellular high mobility group B1 protein (HMGB1) plays a role in regulation of lymphocyte-mediated immune.Lymphocytes originated from mice spleens were stimulated with concentration gradient HMGB1 or combined with ConA in vitro. Then, the proliferation of lymphocytes was assayed with MTT, quantitative and qualitative analysis of apoptosis in lymphocytes and expression of CD3 and CD8 on cells surface and IL-4 and IFN-gamma within cells were assessed using flow cytometry. Levels of interleukin-2 (IL-2) and soluble IL-2R (sIL-2R) of culture supernatant were assayed by ELISA.(1) HMGB1 regulated the proliferation of lymphocytes in a time- and dose-dependent manner, but did not influence the apoptosis of lymphocytes. (2) The ratio of Th to Tc increased from 2.6:1 at culture-hour 0 to 5-7:1 at culture-hour 12 and 24, but that did not change with the stimulation of HMGB1. There were no significant difference in the population and percentage of Th1 and Th2, as well as Tc1 and Tc2, when stimulated with HMGB1. However, HMGB1 in concentrations of 10 and 100 microg/L favored Th1 differentiation, and 1 and 10 microg/L HMGB1 favored Tc1 differentiation. (3) Levels of IL-2 were increased, and sIL-2R decreased, significantly, when stimulated with 10 microg/L HMGB1 for 12 h, thus the ratio of IL-2 to sIL-2R was markedly higher, as compared with 0 and 1000 microg/L HMGB1 (P<0.05 or P<0.01).Low dose HMGB1 could be in favor of the bias of Th1 and Tc1, and improve the lymphocyte-mediated immune.
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