Abstract
BackgroundMicrovascular permeability and leukocyte adhesion are pivotal mechanisms in sepsis pathophysiology contributing to the development of shock and mortality. No effective pharmacological therapy is currently available to restore microvascular barrier function in sepsis. Cholinergic mediators have been demonstrated to exert anti-inflammatory effects during inflammation. Cytidine-5-diphosphocholine (CDP-choline) is an extensively studied cholinergic drug due to its brain protective characteristics in cerebrovascular diseases. This study evaluated the effect of CDP-choline on microvascular permeability and leukocyte adhesion during endotoxemia.MethodsMacromolecular leakage, leukocyte adhesion, and venular wall shear rate were examined in mesenteric postcapillary venules of rats by using intravital microscopy (IVM). Lipopolysaccharide (LPS) (4 mg/kg/h) or equivalent volumes of saline were continuously infused following baseline IVM at 0 min. IVM was repeated after 60 and 120 min in endotoxemic and nonendotoxemic animals. CDP-choline (100 mg/kg) was applied as an i.v. bolus. Animals received either saline alone, CDP-choline alone, CDP-choline 10 min before or 30 min after LPS administration, or LPS alone. Due to nonparametric data distribution, Wilcoxon test and Dunn's multiple comparisons test were used for data analysis. Data were considered statistically significant at p < 0.05.ResultsTreatment with LPS alone significantly increased microvascular permeability and leukocyte adhesion and decreased venular wall shear rate. CDP-choline significantly reduced microvascular permeability in animals treated with LPS. Leukocyte adhesion and venular wall shear rate were not affected by CDP-choline during endotoxemia.ConclusionCDP-choline has a protective effect on microvascular barrier function during endotoxemia. Considering the excellent pharmacologic safety profile of CDP-choline, its use could be an approach for the treatment of capillary leakage in sepsis.
Highlights
Microvascular permeability and leukocyte adhesion are pivotal mechanisms in sepsis pathophysiology contributing to the development of shock and mortality
This study examined the effect of Cytidine-5diphosphocholine (CDP-choline) on microcirculatory alterations during endotoxemia
The key result of this study is that CDP-choline has a protective effect on microvascular permeability during experimental endotoxemia
Summary
Microvascular permeability and leukocyte adhesion are pivotal mechanisms in sepsis pathophysiology contributing to the development of shock and mortality. This study evaluated the effect of CDP-choline on microvascular permeability and leukocyte adhesion during endotoxemia. Inflammatory endothelial cell activation and leukocyteendothelial interactions can be positively influenced by cholinergic mediators [3, 4]. This beneficial cholinergic anti-inflammatory effect on endothelial function can be attributed to the activation of anti-inflammatory neuroimmunological mechanisms described by Tracey et al [5, 6]. CAP-mediated antiinflammatory signals result in the release of acetylcholine (ACh), which interacts with innate immune cells that express the nicotinic acetylcholine receptor subunit α7 (α7nAChR). Human and rat endothelial cells express α7nAChR, identifying the endothelium as a target for anti-inflammatory cholinergic mediators [3, 7]
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