Matrix metalloproteinases: all the RAGE in the acute respiratory distress syndrome
Matrix metalloproteinases: all the RAGE in the acute respiratory distress syndrome
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DOI：
10.1152/ajplung.00023.2011
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发表时间：
2011-04-01
影响因子：
4.9
通讯作者：
Owen, Caroline A.
中科院分区：
文献类型：
--
作者：
Hergrueter, Anja H.;Nguyen, Khoi;Owen, Caroline A.
急性呼吸窘迫综合征（ARDS）的特征是起病迅速、严重的肺部炎症，伴有多形核中性粒细胞（PMNs）大量流入肺部和肺泡毛细血管屏障损伤，并伴有高死亡率。越来越多的证据表明，基质金属蛋白酶（MMPs）参与了ARDS的发病机制。在急性肺损伤（ALI）动物模型中，大多数参与ARDS发病机制的MMPs促进肺部炎症和/或肺泡毛细血管屏障损伤。Yamakawa et al. (23)在这期杂志中的文章是值得注意的，因为它涉及到两种MMP（MMP-3和-13），这两种MMP在ALI或ARDS中迄今尚未得到很好的研究，通过切割一种新的底物：晚期糖基化终末产物（AGEs）的受体来保护肺免受发展中的ALI。MMPs是一个具有多结构域结构的锌依赖性蛋白酶家族。在人类中有23个家庭成员。MMPs由与ARDS发病机制相关的所有细胞类型表达，包括肺泡上皮细胞、PMN、巨噬细胞和成纤维细胞。MMPs与ARDS的发病机制有关，因为ALI和ARDS患者的肺部多种MMPs水平升高，并且一些MMPs的肺部水平与ARDS患者的不良临床结局正相关。例如，在ALI和ARDS患者中，支气管肺泡灌洗液（BAL）中胶原酶（MMP-1、MMP-8和MMP-13）、明胶酶（MMP-2和MMP-9）和基质溶解素-1（MMP-3）的水平升高（9）。MMP-1和MMP-3可能促进ARDS的疾病进展，因为BALF中MMP-1和MMP-3（而非MMP-2、MMP-8或MMP-9）的水平与肺损伤严重程度以及与ARDS患者的多器官衰竭和死亡率呈正相关（9）。尽管在首次鉴定MMP后的数年内，细胞外基质蛋白的降解被认为是MMP的主要功能，但最近在ALI模型中对MMP缺失小鼠的研究表明，MMP通常通过切割细胞因子和趋化因子以调节这些介质的生物活性来促进ALI（表1）。到目前为止，只有两种MMP显示在ALI期间具有抗炎活性：1）MMP-8，其通过降解巨噬细胞炎性蛋白-1 α（18）保护小鼠免受细菌脂多糖（LPS）和高氧诱导的ALI，和2）MMP-13，其通过灭活单核细胞趋化蛋白-1（19）限制高氧诱导的ALI期间的肺部炎症。Yamakawa et al. (23)值得注意的是，
THE ACUTE RESPIRATORY DISTRESS SYNDROME (ARDS) is characterized by rapid-onset, severe lung inflammation with massive influx of polymorphonuclear neutrophils (PMNs) into the lungs and injury to the alveolar capillary barrier and is associated with a high mortality rate. There is mounting evidence that matrix metalloproteinases (MMPs) contribute to the pathogenesis of ARDS. Most MMPs implicated in the pathogenesis of ARDS promote lung inflammation and/or injury to the alveolar capillary barrier in animal models of acute lung injury (ALI). The study of Yamakawa et al.(23) in this issue of the journal is noteworthy because it has implicated two MMPs (MMP-3 and-13), which hitherto have not been well studied in ALI or ARDS, in protecting the lung from developing ALI by cleaving a novel substrate: the receptor for advanced glycation end products (RAGE).MMPs and ARDS pathogenesis. MMPs are a family of zinc-dependent proteinases with a multidomain structure. There are 23 members of this family in humans. MMPs are expressed by all cell types relevant to ARDS pathogenesis including alveolar epithelial cells, PMNs, macrophages, and fibroblasts. MMPs have been implicated in the pathogenesis of ARDS because lung levels of several MMPs are increased in patients with ALI and ARDS and lung levels of some MMPs correlate positively with adverse clinical outcomes in ARDS patients. For example, bronchoalveolar lavage (BAL) fluid (BALF) levels of collagenases (MMP-1,-8, and-13), gelatinases (MMP-2 and-9), and stromelysin-1 (MMP-3) are elevated in patients with ALI and ARDS (9). MMP-1 and-3 may promote disease progression in ARDS since BALF levels of MMP-1 and-3 (but not MMP-2,-8, or-9) correlate positively with lung injury severity and also with multiorgan failure and mortality rates in ARDS patients (9). Although degradation of extracellular matrix proteins was believed to be the main function of MMPs for years after MMPs were first identified, more recent studies of MMP-null mice in models of ALI have shown that MMPs generally promote ALI by cleaving cytokines and chemokines to regulate the biological activities of these mediators (Table 1). Until now, only two MMPs have been shown to possess anti-inflammatory activities during ALI: 1) MMP-8, which protects mice from bacterial lipopolysaccharide (LPS)-and hyperoxia-induced ALI by degrading macrophage inflammatory protein-1α (18), and 2) MMP-13, which limits lung inflammation during hyperoxia-induced ALI by inactivating monocyte chemoattractant protein-1 (19). The study of Yamakawa et al.(23) is noteworthy because it not