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Background Vascular hyporeactivity contributes to hemodynamic alterations and circulatory failure in severe sepsis. Among the identified mechanisms, inflammation and oxidative stress are the most crucial ones in mediating the development of vascular hyporeactivity induced by sepsis. Platonin, a photosensitive dye and an antioxidant, possesses potent antiinflammation effects. We elucidated whether platonin could mitigate vascular hyporeactivity of thoracic aorta in septic rats. Material and methods Adult male Sprague–Dawley rats were randomized to receive sham operation (Sham), Sham plus platonin (100 μg/kg), cecal ligation and puncture (CLP), or CLP plus platonin (10, 50, or 100 μg/kg) and designated as the Sham, P, CLP, CLP + P(10), CLP + P(50), and CLP + P(100) group, respectively ( n = 6 in each group). After maintaining for 12 hours, surviving rats were euthanized and thoracic aorta was isolated and vascular reactivity of aortic rings was determined. Results Vascular reactivity induced by vasoconstrictors phenylephrine and angiotensin II of the Sham and the P groups ( n = 6 in both groups) were similar, whereas vascular reactivity of the CLP group ( n = 5) were significantly lower than those of the Sham group (both P < 0.001). Of note, vascular reactivity induced by phenylephrine and angiotensin II of the CLP + P(10) group ( n = 5) and the CLP group were not significantly different. In contrast, vascular reactivity induced by phenylephrine and angiotensin II of the CLP + P(50) and the CLP + P(100) groups ( n = 6 in both groups) were significantly higher than those of the CLP group (phenylephrine: P = 0.024 and 0.017; angiotensin II: P = 0.031 and 0.036). Conclusion Platonin could mitigate vascular hyporeactivity of thoracic aorta in septic rats. [ABSTRACT FROM AUTHOR]

Abstract: Background: We sought to elucidate whether enhancing phosphoinositide 3-kinase (PI3K)/Akt activity is a crucial mechanism underlying the anti-inflammation effects of magnesium sulfate (MgSO4). Materials and methods: Murine macrophages (RAW264.7 cells) were stimulated with endotoxin, endotoxin plus MgSO4, or endotoxin plus MgSO4 plus PI3K inhibitor (LY294002 or wortmannin). Control groups were run simultaneously. After harvesting, we assayed the expression of inflammatory mediators, transcriptional factor nuclear factor κB (NF-κB), and Akt. Results: MgSO4 significantly attenuated endotoxin-induced upregulation of inflammatory mediators and NF-κB, as macrophages treated with endotoxin plus MgSO4 had significantly lower tumor necrosis factor α (P = 0.022), macrophage inflammatory protein 2 (P = 0.040), phosphorylated (p)-NF-κB p65 (P = 0.003) and p-inhibitor-κB (P < 0.001) concentrations as well as lower NF-κB DNA binding (P = 0.001) than macrophages treated with endotoxin alone. Moreover, macrophages treated with endotoxin plus MgSO4 plus LY294002 or wortmannin had significantly higher tumor necrosis factor α (P = 0.013 and P < 0.001), macrophage inflammatory protein 2 (P = 0.023 and P = 0.003), p-NF-κB p65 (P = 0.006 and P < 0.001), and p-inhibitor-κB (P = 0.001 and P < 0.001) concentrations, as well as higher NF-κB DNA binding (P = 0.038 and P = 0.009), than macrophages treated with endotoxin plus MgSO4, suggesting that PI3K inhibitors reversed these effects of MgSO4. In contrast, macrophages treated with endotoxin plus MgSO4 had significantly higher p-Akt concentration than macrophages treated with endotoxin alone (P = 0.004). Moreover, macrophages treated with endotoxin plus MgSO4 also had significantly higher p-Akt concentration than macrophages treated with endotoxin plus MgSO4 plus LY294002 or wortmannin (P = 0.004 and P < 0.001). Conclusions: Enhancing PI3K/Akt activity is a crucial mechanism underlying the anti-inflammation effects of MgSO4. [Copyright &y& Elsevier]

Abstract: Background: Loss of gut barrier function is crucial in mediating lung injury induced by hemorrhagic shock/resuscitation (HS). High-lipid enteral nutrition (HL) can preserve gut barrier function. We hypothesized that HL could also mitigate HS-induced lung injury. Materials and methods: Forty-eight adult male rats were randomly assigned to one of four experimental groups: HS; HS-HL; Sham; Sham-HL. HS was induced by blood drawing and mean blood pressure was maintained at 40–45 mmHg for 120 min followed by resuscitation with re-infusion of exsanguinated blood/saline mixtures. HL gavage was performed at 45 min before blood drawing and at the end of resuscitation. Results: Intestinal permeability of the HS group was significantly higher than that of the Sham group (P < 0.001). Pulmonary concentrations of malondialdehyde (lipid peroxidation) and inflammatory molecules, including prostaglandin E2, tumor necrosis factor-α, interleukin-6, and macrophage inflammatory protein-2, of the HS group were significantly higher than those of the Sham group. Histologic analyses, including histopathology, wet/dry weight ratio, and neutrophil infiltration revealed moderate lung injury in the HS group. In contrast, intestinal permeability (P < 0.001) and pulmonary concentrations of tumor necrosis factor-α and macrophage inflammatory protein-2 (P = 0.021 and 0.01) of the HS-HL group were significantly lower than those of the HS group. However, pulmonary concentrations of malondialdehyde, prostaglandin E2, and interleukin-6 of the HS-HL and HS groups were comparable. Moreover, histologic analyses also revealed moderate lung injury in the HS-HL group. Conclusions: High-lipid enteral nutrition significantly mitigated gut barrier loss and partially mitigated lung inflammation but not oxidation and lung injury in hemorrhagic shock/resuscitation rats. [Copyright &y& Elsevier]

Abstract: Objectives: We sought to elucidate the effects of vasopressin on modulating the endotoxin-induced upregulation of inflammatory mediators. Materials and Methods: A confluent murine macrophage-like cell line, RAW264.7 cells, were treated with lipopolysaccharide (LPS) (100 ng/mL) or with LPS plus vasopressin (10 pg/mL, 100 pg/mL, or 1000 pg/mL); the cells were denoted as the LPS group, the LPS-V(10) group, the LPS-V(100) group, and the LPS-V(1000) group, respectively. The respective control groups were run simultaneously. Vasopressin was administered immediately after LPS. The expression of inflammatory molecules was then assayed. The molecules that were assayed included the chemokine macrophage-inflammatory protein-2 (MIP-2); the cytokines tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6); nitric oxide (NO)/inducible NO synthase (iNOS); and prostaglandin E2 (PGE2)/cyclooxygenase-2 (COX-2). Results: The differences between the LPS and LPS-V(10) groups in the concentration of inflammatory mediators were not statistically significant. By contrast, the LPS-V(100) and LPS-V(1000) groups were significantly lower than the LPS group in the concentration of MIP-2 (p = 0.004 and p = 0.001, respectively), TNF-α (p = 0.045 and p = 0.007, respectively), IL-1β (p = 0.003 and p < 0.001, respectively), NO (p = 0.014 and p = 0.001, respectively), iNOS mRNA (p = 0.001 and p < 0.001, respectively), PGE2 (p = 0.021 and p < 0.001, respectively), and COX-2 mRNA (p = 0.021 and p = 0.006, respectively). The IL-6 concentration was moreover significantly lower in the LPS-V(1000) group than in the LPS group (p < 0.001), whereas the IL-6 concentration in the LPS-V(100) and the LPS groups was not significantly different. Conclusion: In a dose-dependent manner, vasopressin inhibited the endotoxin-induced upregulation of inflammatory mediators in activated murine macrophages. [Copyright &y& Elsevier]

Background: Lower limb ischemia-reperfusion (I/R) imposes oxidative stress, elicits inflammatory response, and subsequently induces acute lung injury. Ischemic preconditioning (IP), a process of transient I/R, mitigates the acute lung injury induced by I/R. We sought to elucidate whether the protective effects of IP involve heme oxygenase-1 (HO-1). Methods: Adult male rats were randomized to receive I/R, I/R plus IP, I/R plus IP plus the HO-1 inhibitor tin protoporphyrin (SnPP) (n = 12 in each group). Control groups were run simultaneously. I/R was induced by applying rubber band tourniquet high around each thigh for 3 h followed by reperfusion for 3 h. To achieve IP, three cycles of bilateral lower limb I/R (i.e., ischemia for 10 min followed by reperfusion for 10 min) were performed. IP was performed immediately before I/R. After sacrifice, degree of lung injury was determined. Results: Histologic findings, together with assays of leukocyte infiltration (polymorphonuclear leukocytes/alveoli ratio and myeloperoxidase activity) and lung water content (wet/dry weight ratio), confirmed that I/R induced acute lung injury. I/R also caused significant inflammatory response (increases in chemokine, cytokine, and prostaglandin E2 concentrations), imposed significant oxidative stress (increases in nitric oxide and malondialdehyde concentrations), and up-regulated HO-1 expression in lung tissues. IP significantly enhanced HO-1 up-regulation and, in turn, mitigated oxidative stress, inflammatory response, and acute lung injury induced by I/R. In addition, the protective effects of IP were counteracted by SnPP. Conclusions: The protective effects of IP on mitigating acute lung injury induced by lower limb I/R are mediated by HO-1. [Copyright &y& Elsevier]