Angiotensin (1-7) Alleviates Postresuscitation Myocardial Dysfunction by Suppressing Oxidative Stress Through the Phosphoinositide 3-Kinase, Protein Kinase B, and Endothelial Nitric Oxide Synthase Signaling Pathway.

ABSTRACT: There is increasing evidence that angiotensin (1-7) [Ang (1-7)] is an endogenous biologically active component of the renin-angiotensin system. However, the role of the Ang (1-7)-MasR axis in postresuscitation myocardial dysfunction (PRMD) and its associated mechanism are still unclear. In this study, we investigated the effect of the Ang (1-7)-MasR axis on myocardial injury after cardiac arrest-cardiopulmonary resuscitation-restoration of spontaneous circulation. We established a model of oxygen/glucose deprivation-reperfusion in myocardial cells in vitro and a rat model of cardiac arrest-cardiopulmonary resuscitation-restoration of spontaneous circulation in vivo. The cell apoptosis rate and the expression of the superoxide anion 3-nitrotyrosine were decreased in the Ang (1-7) group in vitro and in vivo. The mean arterial pressure was decreased, whereas +LVdp/dtmax and -LVdp/dtmax were increased in rats in the Ang (1-7) group. The mRNA and protein levels of Ang II type 1 receptor, MasR, phosphoinositide 3-kinase, protein kinase B, and endothelial nitric oxide synthase were increased in the Ang (1-7) group in vivo. These results indicate that the Ang (1-7)-MasR axis can alleviate PRMD by reducing myocardial tissue damage and oxidative stress through activation of the phosphoinositide 3-kinase-protein kinase B-endothelial nitric oxide synthase signaling pathway and provide a new direction for the clinical treatment of PRMD.

Effect on extrapulmonary sepsis-induced acute lung injury by hemoperfusion with neutral microporous resin column.

The aim of this study was to investigate the effect of neutral microporous resin hemoperfusion on oxygenation improvement, removal of inflammatory cytokines in plasma and bronchoalveolar lavage, and mortality in acute lung injury induced by extrapulmonary sepsis. Forty-six patients with acute lung injury induced by extrapulmonary sepsis were randomized to HA type hemoperfusion treatment (N=25) or standard therapy (N=21). Those undergoing hemoperfusion treatment received HA330 hemoperfusion. We measured the plasma and bronchoalveolar lavage concentrations of TNF-α and IL-1, and the following parameters were compared between the control group and the hemoperfusion group on days 0, 3 and 7: lung injury measurements (arterial oxygen tension/fractional inspired oxygen ratio, lung injury score, chest X-ray score); interstitial edema of lung (extravascular lung water). Duration of mechanical ventilation, hospital, 28-day, and intensive care unit mortality were also observed. Patients treated with HA hemoperfusion showed a significant removal of plasma and bronchoalveolar lavage TNF-α and IL-1 over time while in the study. Patients in the HA group also demonstrated not only significant improvement of PaO2 /FiO2 , but also decreased Lung Injury Score and chest X-ray score at days 3 and 7. Furthermore, the measurements of the arterial oxygen tension/fractional inspired oxygen ratio, lung injury score and extravascular lung water (EVLWI) significantly correlated with and the concentration of cytokines in the plasma (all P<0.05). The HA hemoperfusion treatment group had a significant reduction in duration of mechanical ventilation, length of intensive care unit stay, and intensive care unit mortality. Significant removal of inflammatory cytokines from circulation and lung by hemoperfusion treatment using the HA type cartridge may contribute to the improvement of lung injury and intensive care unit outcome in extrapulmonary septic patients.

Enhancement of lipopolysaccharide-induced toll-like receptor 2 expression and inflammatory cytokine secretion in HUVECs under high glucose conditions.

AIMS: Endothelial inflammatory responses mediated by toll-like receptors (TLRs) play an important role in atherogenesis. We aimed to investigate the exacerbation of an inflammatory response in human umbilical vein endothelial cells (HUVECs) under high glucose conditions. MAIN METHODS: HUVECs were exposed to normal glucose (5.5 mmol/L) and high glucose (25, 50 mmol/L), alone or with lipopolysaccharide (LPS 0, 10, 100, or 1000 µg/L). Then concentrations of TNF-α and IL-6 in the culture supernatants were determined. The expression of toll-like receptor 2 (TLR2), TLR4 and NF-κB was evaluated by Western blot and RT-PCR analysis. KEY FINDINGS: Compared with the normal glucose group, exposure of HUVECs to 50 mmol/L of glucose or 1000 µg/L of LPS significantly increased the concentrations of TNF-α and IL-6 in the culture supernatants. Neither 25 mmol/L of glucose nor low concentration of LPS (≤100 µg/L) alone had an effect on TNF-α and IL-6 release, or TLR2 expression, but they stimulated the inflammatory response and TLR2 expression under high glucose conditions (25 mmol/L) in combination. LPS (100 µg/L) did not alter the TLR4 expression in HUVECs under high glucose condition. Co-incubation with glucose and LPS increased the nuclear NF-κB expression in endothelial cells. Both NF-κB inhibitor and ROS scavenger could inhibit the enhancement of LPS-induced TLR2 expression and inflammatory cytokine secretion under high glucose conditions. SIGNIFICANCE: We show in vitro data on the potential role of high glucose in increasing LPS-induced TLR2 expression and inflammatory cytokine secretion in HUVECs, offering a new insight into the pathophysiological pathways involved in atherosclerosis.

Dexmedetomidine versus midazolam for the sedation of patients with non-invasive ventilation failure.

OBJECTIVE: To compare the efficacy and safety of sedation with dexmedetomidine vs. midazolam for patients with acute cardiogenic pulmonary edema and hypoxemia during the treatment of non-invasive ventilation (NIV). METHODS: The intensive care unit (ICU) patients treated in our hospital between March 2008 and August 2011 who had acute pulmonary edema and hyoxemia in NIV failure due to patient refusal to continue the NIV sessions (due to discomfort) were enrolled in this study. The patients were divided into two groups by the random numerical table method. They were treated with either midazolam (29 cases) or dexmedetomidine (33 cases). The patients were sedated (Ramsay scale 2-3) by a continuous perfusion of midazolam or dexmedetomidine during the NIV session. Cardiorespiratory and ventilatory parameters, the results of the blood gas analysis, and adverse events were prospectively recorded. The main outcome measure was the percentage of endotracheal intubation during NIV. Secondary endpoints included the duration of non-invasive mechanical ventilation, length of ICU stay, and adverse events. RESULTS: In both groups of patients, the expected sedative scores were obtained. The cardiorespiratory symptoms and signs (oxygenation index, pH value, and respiratory rate) were significantly improved in both groups. In the dexmedetomidine-treated group, the patients had a further decreased percentage of failure of NIV requiring endotracheal intubation (ETI) and a more prolonged mean time to ETI (p=0.042, p=0.024). Furthermore, when compared with the group treated with midazolam, the overall duration of mechanical ventilation and the duration of ICU hospitalization in the group treated with dexmedetomidine were markedly decreased, and weaning from mechanical ventilation was easier (p=0.010, p=0.042). Despite the fact that more dexmedetomidine-treated patients developed bradycardia (18.2% vs. 0, p=0.016), no patients required an intervention or interruption of study drug infusion. Conversely, the incidence of respiratory infections and vomiting was lower in the dexmedetomidine-treated patients (p=0.026, p=0.010). CONCLUSION: Dexmedetomidine led to a more desired level of awaking sedation, shortened the duration of mechanical ventilation and the length of the ICU stay, and further reduced the prevalence of nosocomial infection for NIV sedation in patients with acute cardiogenic pulmonary edema. It appears to provide several advantages and safe control compared with the γ-amino butyric acid (GABA) agonist midazolam.

Relationship between matrix metalloproteinase-2 mRNA expression and clinicopathological and urokinase-type plasminogen activator system parameters and prognosis in human gastric cancer.

AIM: To investigate the relationship between matrix metalloproteinase-2 (MMP-2) mRNA expression and clinicopathologic and urokinase-type plasminogen activator (uPA) system parameter and prognosis in human gastric cancer. METHODS: Expression of MMP-2 mRNA, uPA, and uPA-R mRNA in tumor tissues and > or =5 cm adjacent normal tissues from 67 cases of gastric cancer was studied using RT-PCR and Northern blot respectively. Survival analyses were done using the Kaplan-Meier method. RESULTS: The expression rates of MMP-2 mRNA, uPA and uPA-R mRNA in tumor tissues (31%, 41%, and 51%, respectively) were significantly higher than those in > or =5 cm adjacent tissues (19%, 11%, and 9%; chi(2) = 4.59, 43.58, and 53.24 respectively, P<0.05, 0.0001, and 0.0001, respectively). Expression of MMP-2 mRNA was significantly correlated with lymph node metastasis (metastasis: 61.9%, no metastasis: 39.1%, chi(2) = 7.61, P<0.05), Lauren's classification of diffuse/mixed types: 54.2%, intestinal type: 26.3%, chi(2) = 4.25, P<0.05, expression of uPA and uPA-R mRNA (uPA+: 55.1%, uPA-: 22.2% and uPA-R+: 54.9%, uPA-R-: 18.8%, chi(2) = 5.72 and 6.40 respectively, P<0.05). Kaplan-Meier survival analysis of MMP-2 mRNA expression did not show significant difference in all 67 cases, but revealed an association of the expression of MMP-2 mRNA, uPA, and uPA-R mRNA with worse prognosis (P = 0.0083, 0.0160, and 0.0094, respectively). CONCLUSION: MMP-2 may play an important role in the development of invasion and metastasis of gastric cancer.