Faculty of Medicine, University of Geneva, Geneva, Switzerland.
Am J Physiol Heart Circ Physiol. 2012 Feb 1;302(3):H603-10. doi: 10.1152/ajpheart.00390.2010. Epub 2011 Dec 9.
Persistent ischemia in musculocutaneous tissue may lead to wound breakdown and necrosis. The objective of this experimental study was to analyze, whether the gastric peptide ghrelin prevents musculocutaneous tissue from necrosis and to elucidate underlying mechanisms. Thirty-two C57BL/6 mice equipped with a dorsal skinfold chamber containing ischemic musculocutaneous tissue were allocated to four groups: 1) ghrelin; 2) N(ω)-nitro-l-arginine methyl ester (l-NAME); 3) ghrelin and l-NAME; and 4) control. Microcirculation, inflammation, angiogenesis, and tissue survival were assessed by fluorescence microscopy. Inducible and endothelial nitric oxide synthase (iNOS I and eNOS), vascular endothelial growth factor (VEGF), as well as nuclear factor κB (NF-κB) were assessed by Western blot analysis. Ghrelin-treated animals showed an increased expression of iNOS and eNOS in critically perfused tissue compared with controls. This was associated with arteriolar dilation, increased arteriolar perfusion, and a sustained functional capillary density. Ghrelin further upregulated NF-κB and VEGF and induced angiogenesis. Finally, ghrelin reduced microvascular leukocyte-endothelial cell interactions, apoptosis, and overall tissue necrosis (P < 0.05 vs. control). Inhibition of nitric oxide by l-NAME did not affect the anti-inflammatory and angiogenic action of ghrelin but completely blunted the ghrelin-induced tissue protection by abrogating the arteriolar dilation, the improved capillary perfusion, and the increased tissue survival. Ghrelin prevents critically perfused tissue from ischemic necrosis. Tissue protection is the result of a nitric oxide synthase-mediated improvement of the microcirculation but not due to induction of angiogenesis or attenuation of inflammation. This might represent a promising, noninvasive, and clinically applicable approach to protect musculocutaneous tissue from ischemia.
肌肉皮肤组织的持续缺血可能导致伤口破裂和坏死。本实验研究的目的是分析胃肽 ghrelin 是否能防止肌肉皮肤组织坏死，并阐明其潜在机制。32 只 C57BL/6 小鼠配备了一个含有缺血性肌肉皮肤组织的背部皮褶室，被分为四组：1）ghrelin；2）N(ω)-硝基-l-精氨酸甲酯（l-NAME）；3）ghrelin 和 l-NAME；和 4）对照组。通过荧光显微镜评估微循环、炎症、血管生成和组织存活。通过 Western blot 分析评估诱导型和内皮型一氧化氮合酶（iNOS I 和 eNOS）、血管内皮生长因子（VEGF）以及核因子 κB（NF-κB）。与对照组相比，ghrelin 处理的动物在临界灌注组织中表现出 iNOS 和 eNOS 的表达增加。这与小动脉扩张、小动脉灌注增加和持续的功能性毛细血管密度有关。Ghrelin 进一步上调 NF-κB 和 VEGF 并诱导血管生成。最后，ghrelin 减少了微血管白细胞-内皮细胞相互作用、细胞凋亡和整体组织坏死（与对照组相比，P<0.05）。通过 l-NAME 抑制一氧化氮不影响 ghrelin 的抗炎和血管生成作用，但通过消除小动脉扩张、改善毛细血管灌注和增加组织存活，完全阻断了 ghrelin 诱导的组织保护作用。Ghrelin 可防止临界灌注组织发生缺血性坏死。组织保护是一氧化氮合酶介导的微循环改善的结果，而不是由于诱导血管生成或减轻炎症所致。这可能代表一种有前途的、非侵入性的、临床适用的方法，可保护肌肉皮肤组织免受缺血。
