ABSTRACT
Sepsis is commonly associated with loss of microvascular endothelial barrier function (capillary leak) and dysfunctional microcirculation, which both promote organ failure. The development of a distinct therapy of impaired endothelial barrier function and disturbed microcirculation is highly relevant because both of these phenomena constitute crucial processes which critically influence the prognosis of patients. Numerous in vivo and in vitro trials over the past years have fostered a better understanding of the pathophysiology of capillary leak. Furthermore, promising data in animal models show that therapeutic modulation of endothelial barrier function and microcirculation can be achieved by stabilizing endothelial cAMP (cyclic adenosine monophosphate) levels followed by activation of Rho-GTPase Rac1, e. g. by phosphodiesterase 4 inhibitors. This review summarizes and discusses recent findings of cellular mechanisms and in vivo trials.
Subject(s)
Capillary Leak Syndrome/drug therapy , Endothelium, Vascular/drug effects , Microcirculation/drug effects , Phosphodiesterase 4 Inhibitors/therapeutic use , Sepsis/drug therapy , Sepsis/physiopathology , Animals , Humans , Prognosis , Vascular Diseases/drug therapy , Vascular Diseases/physiopathologyABSTRACT
BACKGROUND: Anaesthetic-induced (APOST) and ischaemic postconditioning (IPOST) against myocardial infarction are mediated via phosphatidylinositol-3-kinase/Akt. Pim-1 kinase is acting downstream of Akt and has recently been demonstrated to enhance cardiomyocyte survival. We tested the hypothesis that both APOST and IPOST are mediated by Pim-1 kinase. METHODS: Pentobarbital-anaesthetized male C57BL/6 mice were subjected to 45-min coronary artery occlusion (CAO) and 3-h reperfusion. Animals received either no intervention, the Pim-1 kinase inhibitor II (10 µg/g intraperitoneally) or its vehicle dimethy sulfoxide (10 µl/g intraperitoneally). Three minutes prior to the end of CAO, 1.0 minimum alveolar concentration desflurane was administered for 18 min alone or in combination with Pim-1 kinase inhibitor II. IPOST was induced by three cycles of each 10-s ischaemia/reperfusion, and animals received either IPOST alone or in combination with Pim-1 kinase inhibitor II. Infarct size was determined with triphenyltetrazolium chloride and area at risk with Evans blue. Protein expression of Pim-1 kinase, Bad, phospho-Bad(Ser112) and B-cell lymphoma 2 was determined using Western immunoblotting analysis. RESULTS: Infarct size in control animals (CON) was 46 ± 3%. Dimethylsulfoxide (47 ± 3%) and Pim-1 kinase inhibitor II (44 ± 5%) did not significantly reduce infarct size. Desflurane (16 ± 2%*; *P < 0.05 vs. CON) and IPOST (21 ± 2%*) significantly reduced infarct size compared with CON. Inhibition of Pim-1 kinase abolished desflurane-induced postconditioning (46 ± 4%) and IPOST (44 ± 5%). Western blot analysis revealed that only desflurane enhances phosphorylation of Bad at serine 112 that was abrogated by Pim-1 kinase inhibitor II. CONCLUSION: These data suggest that Pim-1 kinase mediates both desflurane-induced postconditioning and IPOST in mice.
