Cytoprotective pathways in the vascular endothelium. Do they represent a viable therapeutic target?

The vascular endothelium is a critical interface, which separates the organs from the blood and its contents. The endothelium has a wide variety of functions and maintenance of endothelial homeostasis is a multi-dimensional active process, disruption of which has potentially deleterious consequences if not reversed. Vascular injury predisposes to endothelial apoptosis, dysfunction and development of atherosclerosis. Endothelial dysfunction is an end-point, a central feature of which is increased ROS generation, a reduction in endothelial nitric oxide synthase and increased nitric oxide consumption. A dysfunctional endothelium is a common feature of diseases including rheumatoid arthritis, systemic lupus erythematosus, diabetes mellitus and chronic renal impairment. The endothelium is endowed with a variety of constitutive and inducible mechanisms that act to minimise injury and facilitate repair. Endothelial cytoprotection can be enhanced by exogenous factors such as vascular endothelial growth factor, prostacyclin and laminar shear stress. Target genes include endothelial nitric oxide synthase, heme oxygenase-1, A20 and anti-apoptotic members of the B cell lymphoma protein-2 family. In light of the importance of endothelial function, and the link between its disruption and the risk of atherothrombosis, interest has focused on therapeutic conditioning and reversal of endothelial dysfunction. A detailed understanding of cytoprotective signalling pathways, their regulation and target genes is now required to identify novel therapeutic targets. The ultimate aim is to add vasculoprotection to current therapeutic strategies for systemic inflammatory diseases, in an attempt to reduce vascular injury and prevent or retard atherogenesis

Effects of Biliverdin Administration on Acute Lung Injury Induced by Hemorrhagic Shock and Resuscitation in Rats

Hemorrhagic shock and resuscitation induces pulmonary inflammation that leads to acute lung injury. Biliverdin, a metabolite of heme catabolism, has been shown to have potent cytoprotective, anti-inflammatory, and anti-oxidant effects. This study aimed to examine the effects of intravenous biliverdin administration on lung injury induced by hemorrhagic shock and resuscitation in rats. Biliverdin or vehicle was administered to the rats 1 h before sham or hemorrhagic shock-inducing surgery. The sham-operated rats underwent all surgical procedures except bleeding. To induce hemorrhagic shock, rats were bled to achieve a mean arterial pressure of 30 mmHg that was maintained for 60 min, followed by resuscitation with shed blood. Histopathological changes in the lungs were evaluated by histopathological scoring analysis. Inflammatory gene expression was determined by Northern blot analysis, and oxidative DNA damage was assessed by measuring 8-hydroxy-2' deoxyguanosine levels in the lungs. Hemorrhagic shock and resuscitation resulted in prominent histopathological damage, including congestion, edema, cellular infiltration, and hemorrhage. Biliverdin administration prior to hemorrhagic shock and resuscitation significantly ameliorated these lung injuries as judged by histopathological improvement. After hemorrhagic shock and resuscitation, inflammatory gene expression of tumor necrosis factor-alpha and inducible nitric oxide synthase were increased by 18- and 8-fold, respectively. Inflammatory gene expression significantly decreased when biliverdin was administered prior to hemorrhagic shock and resuscitation. Moreover, after hemorrhagic shock and resuscitation, lung 8-hydroxy-2' deoxyguanosine levels in mitochondrial DNA expressed in the pulmonary interstitium increased by 1.5-fold. Biliverdin administration prior to hemorrhagic shock and resuscitation decreased mitochondrial 8-hydroxy-2' deoxyguanosine levels to almost the same level as that in the control animals. We also confirmed that biliverdin administration after hemorrhagic shock and resuscitation had protective effects on lung injury. Our findings suggest that biliverdin has a protective role, at least in part, against hemorrhagic shock and resuscitation-induced lung injury through anti-inflammatory and anti-oxidant mechanisms