Adipose tissue inflammation and coagulation in humans

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Medicine

Sammanfattning: Background Adipose tissue (AT) is not only a store of energy but an endocrine organ with capacity to produce and release proinflammatory mediators into the circulation. Obesity is an inflammatory disease, with increased circulating levels of interleukin (IL)-6, due to synthesis in AT. As current knowledge regarding AT inflammation, to a great extent relies on studies done in nonstimulated or chronic inflammatory conditions, it is important to add data from human studies, using different models of induced acute systemic inflammation. As obesity is becoming a global disease it is also an increasing risk factor for cardiovascular disease (CVD). CVD events are known complications after surgery and severe infection. The mechanisms behind this increased risk are still poorly understood but an acute systemic inflammation is a common denominator. Methods and results Study I: We investigated if a standardised systemic inflammation, induced by a vaccination against Salmonella typhi, would trigger inflammatory gene expression in AT. Healthy volunteers were investigated whereof half of them were vaccinated. Plasma levels of IL-6 increased 8 hrs after vaccination. In peripheral blood mononuclear cells we found an increased tumour necrosis factor gene expression after 4 hrs. In AT there were no differences in gene expression between the two groups. Study II: Gene expression and production of inflammatory mediators in different AT depots were investigated after open heart surgery. Plasma levels of IL-6 increased 25-fold. In both omental and subcutaneous AT, we found a strong upregulation of nuclear factor-?B regulated genes. Immunohistochemistry (IHC) showed staining for E-selectin associated with a high number of macrophages in close contact with and in the vascular wall. Increased levels of IL-6 were detected in microdialysate from subcutaneous AT. Study III: Plasminogen activator inhibitor-1 (PAI-1) synthesis in AT was studied after acute systemic inflammation, induced by open heart surgery. Gene expression of PAI-1 increased 27-fold in omental AT and 3-fold in subcutaneous AT. After surgery, IHC staining showed localization of PAI-1 antigen within endothelial cells, in the AT interstitium close to AT vessels and in solitary cells between the adipocytes. The upregulated gene expression and protein synthesis in AT was followed by increased concentrations of PAI-1 antigen in plasma. Study IV: This was a sub-study of study I and II, with the aim to investigate the effects of an acute systemic inflammation on adiponectin and leptin synthesis. Neither plasma levels of adiponectin nor leptin were changed after vaccination. Gene expression of adiponectin and leptin were unaltered in both omental and subcutaneous AT after surgery. Conclusion Vaccination stimulates a mild systemic inflammation but does not trigger proinflammatory gene expression in AT. Open heart surgery induced a strong inflammatory response in both omental and subcutaneous AT including adhesion of macrophages to an activated endothelium and release of IL-6 from AT interstitium. We found no evidence that an acute systemic inflammation could affect synthesis of adiponectin or leptin indicating that these two adipokines are not key elements in the early acute-phase response. There was a markedly increased gene expression and protein synthesis of PAI-1 in human AT after open heart surgery. The increase was most prominent in omental AT. PAI-1 synthesis in AT, following acute systemic inflammation, may be the link between inflammation and impaired fibrinolysis that might explain the increased risk for myocardial infarction after surgery or infection.

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