Impact of lipid modulation on the intestinal microcirculation in experimental sepsis.

It has been observed, that patients who were treated medically for dyslipoproteinemia had a potentially lower risk of complications during infection and sepsis, regarding both morbidity and mortality. Aim of this study in experimental sepsis was to elucidate the impact of lipid metabolism modulation by simvastatin, HDL, or bezafibrate, respectively, on the intestinal microcirculation which plays a crucial role in the development of multiple organ failure in sepsis. Experimental sepsis was induced in Lewis rats by intravenous lipopolysaccharide (LPS) administration. Animals were treated with simvastatin, HDL or bezafibrate. By means of intestinal intravital microscopy (IVM), the inflammatory response in the microcirculation was studied by leukocyte adherence assessment (LA) and functional capillary density (FCD) measurements. In addition, plasma levels of pro-inflammatory cytokines were determined. Bezafibrate treatment led to a reduction in leukocyte adherence, improved functional capillary density (FCD), and a reduction in interleukin-1α (IL-1α), tumour necrosis factor α (TNF-α) and granulocyte macrophage colony stimulating factors (GM-CSF) plasma levels in experimental sepsis. Contrary to this, the administration of HDL increased leukocyte adherence as well as the number of rolling leukocytes. Only IL-1α plasma levels were decreased by HDL. No significant changes were observed following simvastatin treatment. In summary, only bezafibrate showed anti-inflammatory effects in endotoxemia. This effect cannot be explained by the HDL-enhancing effect of the bezafibrate, since the direct administration of HDL showed opposite effects. Bezafibrate induced reduction of inflammation in sepsis should be investigated in further studies.

Impact of insulin on the intestinal microcirculation in a model of sepsis-related hyperglycemia.

BACKGROUND: Sepsis involves dysfunctional glucose metabolism. Among patients with sepsis, hyperglycemia is frequent and insulin administration has been evaluated for glycemic control to improve patient outcomes. Only few studies have examined the hyperglycemic microcirculation and the impact of insulin on the microvasculature in sepsis. OBJECTIVE: To study the functional capillary density (FCD) and leukocyte activation within the intestinal microcirculation in endotoxin-induced experimental sepsis. METHODS: In 50 male Lewis rats, endotoxemia was induced with lipopolysaccharide (LPS; 5 mg/kg). Low dose (LD) glucose was administered to avoid insulin-induced hypoglycemia. High dose (HD) glucose was administered to model sepsis-related hyperglycemia. Animals in LD and HD glucose groups received an insulin bolus (1.4 IU/kg). Two hours after LPS administration, intravital microscopy (IVM) of the terminal ileum was performed, and FCD and leukocyte adherence were measured in a blinded fashion. Blood glucose levels were measured every 30 min following the onset of endotoxemia. Plasma samples were collected 3 h after the onset of endotoxemia to measure IFN-γ, TNF-α, IL-1α, IL-4, GM-CSF and MCP-1 levels using multiplex bead immunoassay. RESULTS: Endotoxemia significantly reduced FCD and increased leukocyte adherence within the intestinal microvasculature. LD and HD glucose administration combined with insulin improved the FCD and decreased the adherence of leukocytes in endotoxemic animals as did HD glucose administration alone. Consistent with these results, IL-4, IL-1α, GM-CSF and IFN-γ levels were decreased following combined HD glucose and insulin administration in endotoxemic animals. CONCLUSIONS: Insulin administration, as well as an endogenous insulin response triggered by HD glucose administration, improved the FCD and decreased leukocyte activation in endotoxemic rats. The results of this study give insight into the immune and vaso-modulatory role of insulin administration during experimental endotoxemia, and may be extrapolated for clinical sepsis and other critical illnesses with marked microcirculatory dysfunction.

Effect of deletion of cIAP2 on intestinal microcirculation in mouse endotoxemia and polybacterial sepsis.

Deletion of the cellular inhibitor of apoptosis protein 2 (cIAP2) is capable of rendering lipopolysaccharide (LPS)-activated macrophages highly susceptible to apoptotic triggers, thereby quickly eliminating the resident macrophage population soon after the initiation of a systemic inflammatory response. The aim of our study was to evaluate the impact of cIAP2 deletion on leukocyte recruitment and capillary perfusion in experimental endotoxemia and polybacterial sepsis using intravital microscopy of the intestinal microcirculation, which is crucial in the pathogenesis of septic multiple organ failure. We studied six groups of animals: wild-type (WT) control mice, cIAP2 knockout mice, endotoxemic WT mice (5 mg/kg LPS), endotoxemic cIAP2 knockouts (5 or 50 mg/kg LPS, respectively), and WT as well as knockout mice with polybacterial sepsis (colon ascendens stent peritonitis [CASP]). Intravital microscopy of the intestinal microcirculation was performed after 1 h of endotoxemia or 12 h of CASP-induced sepsis, respectively. Intestinal microvascular blood flow was measured using laser Doppler flowmetry. After 1 h of endotoxemia (5 mg/kg LPS), we observed a significant increase of leukocyte adhesion in intestinal submucosal venules of WT mice in comparison with control animals. The cIAP2 knockout mice showed a significant reduction in leukocyte recruitment within the intestinal submucosal microvasculature after 5 or 50 mg/kg LPS challenge, respectively. Lipopolysaccharide-induced decrease in intestinal microvascular blood flow was not affected by cIAP2 inhibition. In CASP-induced sepsis, cIAP2 deletion had no effect on intestinal leukocyte recruitment. Deletion of cIAP2 resulted in reduced microvascular leukocyte recruitment within the intestinal microcirculation in endotoxemia but not in polybacterial sepsis.