BackgroundIschemic postconditioning (IPO) has been demonstrated to attenuate ischemia/reperfusion (I/R) injury in the heart and brain, its roles to liver remain to be defined. The study was undertaken to determine if IPO would attenuate liver warm I/R injury and its protective mechanism.MethodsMice were divided into sham, I/R, IPO+I/R (occlusing the porta hepatis for 60 min, then treated for three cycles of 10 sec brief reperfusion consecutively, followed by a persistent reperfusion); L-NAME+ sham (L-NAME, 16 mg/kg, i.v., 5 min before repefusion); L-NAME+I/R; and L-NAME+ IPO. Blood flow of caudate and left lobe of the liver was blocked. Functional and morphologic changes of livers were evaluated. Contents of nitric oxide, eNOS and iNOS in serum were assayed. Concentration of eNOS, iNOS, malondialdehyde (MDA) and activity of superoxide dismutase (SOD) in hepatic tissue were also measured. Expressions of Akt, p-Akt and HIF-1α protein were determined by western blot. Expressions of TNF-α and ICAM-1 were measured by immunohistochemistry and RT-PCR.ResultsIPO attenuated the dramatically functional and morphological injuries. The levels of ALT was significantly reduced in IPO+I/R group (p < 0.05). Contents of nitric oxide and eNOS in serum were increased in the IPO+I/R group (p < 0.05). IPO also up-regulated the concentration of eNOS, activity of SOD in hepatic tissue (p < 0.05), while reduced the concentration of MDA (p < 0.05). Moreover, protein expressions of HIF-1α and p-Akt were markedly enhanced in IPO+I/R group. Protein and mRNA expression of TNF-α and ICAM-1 were markedly suppressed by IPO (p < 0.05). These protective effects of IPO could be abolished by L-NAME.ConclusionsWe found that IPO increased the content of NO and attenuated the overproduction of ROS and I/R-induced inflammation. Increased NO contents may contribute to increasing HIF-1α level, and HIF-1α and NO would simultaneously protect liver from I/R injury. These findings suggested IPO may have the therapeutic potential through Akt-eNOS-NO-HIF pathway for the better management of liver I/R injury.

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Rho family guanosine triphosphatase (GTPase) 3 (Rnd3), a member of the small Rho GTPase family, has been suggested to regulate cell actin cytoskeleton dynamics, cell migration, and apoptosis through the Rho kinase-dependent signaling pathway. The biological function of Rnd3 in the heart is unknown. The downregulation of small GTPase Rnd3 transcripts was found in patients with end-stage heart failure. The pathological significance of Rnd3 loss in the transition to heart failure remains unexplored. To investigate the functional consequence of Rnd3 downregulation and the associated molecular mechanism, we generated Rnd3+/− haploinsufficient mice to mimic the downregulation of Rnd3 observed in the failing human heart. Rnd3+/− mice were viable; however, the mice developed heart failure after pressure overload by transverse aortic constriction (TAC). Remarkable apoptosis, increased caspase-3 activity, and elevated Rho kinase activity were detected in the Rnd3+/− haploinsufficient animal hearts. Pharmacological inhibition of Rho kinase by fasudil treatment partially improved Rnd3+/− mouse cardiac functions and attenuated myocardial apoptosis. To determine if Rho-associated coiled-coil kinase 1 (ROCK1) was responsible for Rnd3 deficiency-mediated apoptotic cardiomyopathy, we established a double-knockout mouse line, the Rnd3 haploinsufficient mice with ROCK1-null background (Rnd3+/−/ROCK1−/−). Again, genetic deletion of ROCK1 partially but not completely rescued Rnd3 deficiency-mediated heart failure phenotype. These data suggest that downregulation of Rnd3 correlates with cardiac loss of function as in heart failure patients. Animals with Rnd3 haploinsufficiency are predisposed to hemodynamic stress. Hyperactivation of Rho kinase activity is responsible in part for the apoptotic cardiomyopathy development. Further investigation of ROCK1-independent mechanisms in Rnd3-mediated cardiac remodeling should be the focus for future study.

Background/Aims Hematocrit is a widely used biomarker to guide early fluid therapy for patients with acute pancreatitis (AP), but there is controversy over whether early rapid fluid therapy (ERFT) should be used in hemoconcentrated patients. This study investigated the association of hematocrit and ERFT with clinical outcomes of patients with AP. Methods Data from prospectively maintained AP database and retrospectively collected fluid management details were stratified according to actual severity defined by revised Atlanta classification. Hemoconcentration and "early" were defined as hematocrit > 44% and the first 6 h of general ward admission, respectively, and "rapid" fluid rate was defined as ≥ 3 ml/ kg/h. Patients were allocated into 4 groups for comparisons: group A, hematocrit ≤ 44% and fluid rate < 3 ml/kg/h; group B, hematocrit ≤ 44% and fluid rate ≥ 3 ml/kg/h; group C, hematocrit > 44% and fluid rate < 3 ml/kg/h; and group D, hematocrit > 44% and fluid rate ≥ 3 ml/kg/h. Primary outcome was rate of noninvasive positive-pressure ventilation (NPPV). Results A total of 912 consecutive AP patients were analyzed. ERFT has no impact on clinical outcomes of hemoconcentrated, non-severe or all non-hemoconcentrated AP patients. In hemoconcentrated patients with severe AP (SAP), ERFT was accompanied with increased risk of NPPV (odds ratio 5.96, 95% CI 1.57-22.6). Multivariate regression analyses confirmed ERFT and hemoconcentration were significantly and independently associated with persistent organ failure and mortality in patients with SAP. Conclusions ERFT is associated with increased rate of NPPV in hemoconcentrated patients with SAP.

TRQI could improved the Chinese medical signs and symptoms in the patients with AECOPD, possibly because of the decreasing plasma levels of IL-8 and NE which could improve response to airway inflammation and mucus hypersecretion.