Activated protein C improves pial microcirculation in experimental endotoxemia in rats

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• 作者：Juan Zhou^a ; ^b ; ¹ ; Dragan Pavlovic^d ; ¹ ; Julia Willecke^d ; Claudius Friedel^e ; Sara Whynot^a ; Orlando Hung^a ; ^c ; Vladimir Cerny^a ; ^f ; Henry Schroeder^e ; Michael Wendt^d ; Romesh Shukla^a ; Christian Lehmann^a ; ^b ; ^c ; ^d ; ^{chlehmann@mac.com}
• 关键词：rhAPC ; Recombinant human activated protein C ; FCD ; Functional capillary density ; DCD ; Dysfunctional capillary density ; NCD ; Nonfunctional capillary density ; IVM ; Fluorescent intravital microscopy
• 刊名：Microvascular Research
• 出版年：2012
• 出版时间：May, 2012
• 年：2012
• 卷：83
• 期：3
• 页码：276-280
• 全文大小：494 K

文摘

Introduction

The brain is one of the first organs affected clinically in sepsis. Microcirculatory alterations are suggested to be a critical component in the pathophysiology of sepsis. The aim of this study was to investigate the effects of recombinant human activated protein C (rhAPC) on the pial microcirculation in experimental endotoxemia using intravital microscopy. Our hypothesis is rhAPC protects pial microcirculation in endotoxemia.

Methods

Endotoxemia was generated in Lewis rats with intravenous injection of lipopolysaccharide (LPS, 5 mg/kg i.v.). Dura mater was removed through a cranial window to expose pial vessels on the brain surface. The microcirculation, including leukocyte-endothelial interaction, functional capillary density (FCD) and plasma extravasation of pial vessels was examined by fluorescent intravital microscopy (IVM) 2 h after administration of LPS, LPS and rhAPC or equivalent amount of saline (used as Control group). Plasma cytokine levels of interleukin 1 alpha (IL1-¦Á), tumor necrosis factor-¦Á (TNF-¦Á), interferon ¦Ã (IFN-¦Ã), Monocyte chemotactic protein-1 (MCP-1) and Granulocyte-macrophage colony-stimulating factor (GM-CSF) were evaluated after IVM.

Results

LPS challenge significantly increased leukocyte adhesion (773 ¡À 190 vs. 592 ¡À 152 n/mm² Control), decreased FCD (218 ¡À 54 vs. 418 ¡À 74 cm/cm² Control) and increased proinflammatory cytokine levels (IL-1¦Á: 5032 ¡À 1502 vs. 8 ¡À 21 pg/ml; TNF-¦Á: 1823 ¡À 1007 vs. 168 ¡À 228 pg/ml; IFN-¦Ã: 785 ¡À 434 vs. 0 pg/ml; GM-CSF: 54 ¡À 52 vs. 1 ¡À 3 pg/ml) compared to control animals. rhAPC treatment significantly reduced leukocyte adhesion (599 ¡À 111 n/mm²), increased FCD (516 ¡À 118 cm/cm²) and reduced IL-1¦Á levels (2134 ¡À 937 pg/ml) in the endotoxemic rats.

Conclusion

APC treatment significantly improves pial microcirculation by reducing leukocyte adhesion and increasing FCD.