Nedrebø Torbjørn, Karlsen Tine V, Salvesen Gerd S, Reed Rolf K
Division for Physiology, Department of Biomedicine, University of Bergen, Jonas Lies vei 91, N-5009 Bergen, Norway.
J Physiol. 2004 Sep 1;559(Pt 2):583-91. doi: 10.1113/jphysiol.2004.067751. Epub 2004 Jul 2.
In this study we present a novel function of insulin in rat dermis. We investigated local effects of insulin on interstitial fluid pressure (Pif), and capillary albumin leakage and pro-inflammatory cytokine production in skin and serum after intravenous lipopolysaccharide (LPS), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) challenge treated with a glucose-insulin-potassium regimen (GIK). The main objective for this study was to investigate anti-inflammatory effects of insulin. Work by others shows that insulin stimulates cell adhesion, and that this effect is dependent upon phosphatidylinositol 3-kinase (PI3K) activity. Cytokines like platelet-derived growth factor BB (PDGF-BB) attenuate lowering of Pif, possibly via PI3K. LPS and pro-inflammatory cytokines contribute to oedema development during acute inflammation by lowering the Pif. Intravenous injection of LPS, TNF-alpha or IL-1beta to Wistar Møller rats caused a lowering of Pif, but after local injection of insulin in the paw, Pif increased back to control values. IL-1beta caused a lowering in control from -0.5 +/- 0.2 mmHg to -3.0 +/- 0.2 mmHg after 20 min (mean +/- S.E.M.) (P < 0.05). Within 50 min after insulin injection the pressure was increased to -0.6 +/- 0.2 mmHg (P > 0.05 compared with control). Insulin was given together with a PI3K inhibitor (wortmannin) locally in the skin, almost abolishing the effect of insulin on Pif. A GIK regimen was given as a continuous intravenous infusion, significantly attenuating the oedema formation after LPS or TNF-alpha/IL-1beta challenge. The same GIK regimen caused a significant reduction in pro-inflammatory cytokines in serum and in interstitial fluid in skin of endotoxaemic rats. These experiments show a possible role for insulin in the interstitium during inflammation induced by LPS and TNF-alpha/IL-1beta. Insulin can attenuate a lowering of Pif possibly via PI3K, and it has an anti-inflammatory effect by inhibiting production of pro-inflammatory cytokines.
在本研究中，我们展示了胰岛素在大鼠真皮中的一种新功能。我们研究了胰岛素对间质液压力（Pif）的局部影响，以及静脉注射脂多糖（LPS）、肿瘤坏死因子-α（TNF-α）和白细胞介素-1β（IL-1β）后，经葡萄糖-胰岛素-钾方案（GIK）处理的皮肤和血清中的毛细血管白蛋白渗漏及促炎细胞因子产生情况。本研究的主要目的是探究胰岛素的抗炎作用。其他人的研究表明胰岛素能刺激细胞黏附，且该效应依赖于磷脂酰肌醇3-激酶（PI3K）活性。像血小板衍生生长因子BB（PDGF-BB）这样的细胞因子可能通过PI3K减弱Pif的降低。LPS和促炎细胞因子通过降低Pif导致急性炎症期间的水肿形成。给Wistar Møller大鼠静脉注射LPS、TNF-α或IL-1β会导致Pif降低，但在爪部局部注射胰岛素后，Pif回升至对照值。IL-1β使对照在20分钟后从-0.5±0.2 mmHg降至-3.0±0.2 mmHg（平均值±标准误）（P<0.05）。在注射胰岛素后50分钟内，压力升至-0.6±0.2 mmHg（与对照相比，P>0.0）。在皮肤局部将胰岛素与PI3K抑制剂（渥曼青霉素）一起给予，几乎消除了胰岛素对Pif的作用。以连续静脉输注的方式给予GIK方案，可显著减轻LPS或TNF-α/IL-1β刺激后的水肿形成。相同的GIK方案使内毒素血症大鼠血清和皮肤间质液中的促炎细胞因子显著减少。这些实验表明胰岛素在LPS和TNF-α/IL-1β诱导的炎症期间的间质中可能发挥作用。胰岛素可能通过PI3K减弱Pif的降低，并且通过抑制促炎细胞因子的产生具有抗炎作用。
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