Is Matrix Metalloproteinase-8 Activity in the Mucosal Barrier a Requirement for Leakage of Cecal Material in Peritonitis?
Is Matrix Metalloproteinase-8 Activity in the Mucosal Barrier a Requirement for Leakage of Cecal Material in Peritonitis?
复制标题
粘膜屏障中的基质金属蛋白酶 8 活性是腹膜炎盲肠物质渗漏的必要条件吗？
DOI：
10.1097/ccm.0000000000001500
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发表时间：
2016
影响因子：
8.8
通讯作者：
Schmid-Schönbein,GeertW
中科院分区：
文献类型：
--
作者：
Schmid-Schönbein,GeertW
基质金属蛋白酶(MMPs)参与多种结构和免疫功能。它们存在于许多细胞类型中，包括正常肠道的上皮粘膜屏障。基于先前的证据表明基质金属蛋白酶-8(一种胶原酶)在小儿败血症患者的生存以及盲肠结扎模型中的生存中的作用(1，2)，在这一期的危重护理医学中，Atkinson等人(3)集中在肠道和髓系细胞中的基质金属蛋白酶-8。然而，对于体内MMPs的生理和病理生理功能的详细分析，由于缺乏没有靶外作用的特异性抑制剂而受到阻碍。因此，为了获得进一步的机械洞察力，这些研究人员提出了一个有趣的建议，其中包括一个实验设计，使用遗传方法结合器官/组织交换与野生型小鼠。利用一只MMP8基因敲除的小鼠，作者报道盲肠固有的MMP8，而不是髓系细胞(如中性粒细胞)中的MMP8，在盲肠结扎穿孔(CLP)诱导的腹膜炎后起到了生存的作用。通过在野生型和MMP8缺失小鼠之间的盲肠囊进行器官移植实验，作者报告说，这些组织中的MMP8是继发于肠道损害的败血症CLP介导的腹膜炎的关键成分。与野生型盲肠相比，腹膜内植入穿孔的基质金属蛋白酶-8空盲肠具有生存优势。换句话说，盲肠中的基质金属蛋白酶-8参与了腹膜炎的致死性进展。基质金属蛋白酶-8可能是一种促炎介质。但这一假设并没有得到文献的一致支持，在这些文献中，观察到基质金属蛋白酶-8可以增强和在某些情况下降低炎症标志物(4)。因此，肠内基质金属蛋白酶-8可能介导CLP诱导的腹膜炎致死性进展的机制(S)仍不清楚。如果一种可溶形式的基质金属蛋白酶-8本身导致
Matrix metalloproteinases (MMPs) participate in a variety of structural and immunological functions. They are present in many cell types, including the epithelial mucosal barrier of a normal intestine. Based on previous evidence suggesting a role of MMP-8 (a collagenase) in survival of pediatric septic patients as well as survival in a cecal ligation model (1, 2), in this issue of Critical Care Medicine, Atkinson et al (3) have focused on MMP-8 in the intestine and in myeloid cells. Detailed analysis of physiologic and pathophysiologic functions of MMPs in vivo is, however, hampered by the lack of specific inhibitors without off-target effects. Thus, to gain further mechanistic insight, these investigators present an interesting proposal with an experimental design that uses a genetic approach in combination with organ/tissue exchanges with a wild-type mouse. Using an MMP-8 gene knockdown mouse, the authors report that the MMP-8 inherent to the cecum, and less the MMP-8 in myeloid cells (eg, neutrophils), plays a role in survival after cecal ligation puncture (CLP)–induced peritonitis. Using additional organ transfer experiments with cecal pouches between a wild-type and an MMP-8 null mouse, the authors report that MMP-8 in these tissues is a critical component of septic CLP-mediated peritonitis secondary to intestinal compromise. Intraperitoneal implantation of a punctured MMP-8 null cecum provides a survival advantage when compared with a wild-type cecum. In other words, the MMP-8 in the cecum is involved in the lethal progression of peritonitis. MMP-8 may be serving as a proinflammatory mediator. But this hypothesis is not uniformly supported by the literature in which MMP-8 has been observed to enhance and, in some cases, reduce markers for inflammation (4). Thus, the mechanism (s) by which MMP-8 in the intestine may mediate a lethal progression in CLP-induced peritonitis remains unknown. If a soluble form of MMP-8 itself causes