Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects
Alpha-1-antitrypsin and a broad spectrum metalloprotease inhibitor, RS113456, have similar acute anti-inflammatory effects
复制标题
DOI：
10.1038/labinvest.3780324
复制
发表时间：
2001-08-01
影响因子：
5
通讯作者：
Wright, JL
中科院分区：
文献类型：
--
作者：
Churg, A;Dai, J;Wright, JL
越来越多的证据表明，抗蛋白酶能够影响炎症反应。为了进一步研究这个问题，我们给C57小鼠注射了人抗胰蛋白酶（al AT）或合成金属蛋白酶抑制剂（RS113456），随后给C57小鼠注射了单剂量的气管内石英，石英是一种引起明显的、持久的、多形核白细胞（PMN）浸润的粉尘。在给药2小时后，两种抗蛋白酶完全抑制二氧化硅诱导的PMN流入肺部和巨噬细胞炎症蛋白-2 (MIP-2)/单核细胞趋化蛋白-1 (MCP-1)（中性粒细胞/巨噬细胞趋化剂）基因表达，部分抑制核转录因子kappaB （NF-kappaB）易位，增加NF-kappaB抑制剂（I kappaB）水平。抗蛋白酶治疗后24小时，PMN内流和结缔组织破坏（以灌洗氨基葡萄糖或羟脯氨酸测量）仍处于或接近控制水平，NF-kappaB易位和MIP-2/MCP-1基因表达的增加受到不同程度的抑制。在这两个时间点，两种药物都不能阻止二氧化硅诱导的全肺MIP-2或MCP-1蛋白量的增加，但两者都能阻止24小时全肺细胞间粘附分子-1 （ICAM-1）的增加。通过氧化使α 1AT失活到不再具有抗蛋白水解特性的程度，并不影响其抑制炎症的能力。在巨噬细胞金属弹性酶（MME -/-）基因敲除的小鼠中，这两种抗蛋白酶也能阻止硅诱导的急性炎症反应，小鼠出现炎症，但没有结缔组织破坏，α 1AT分解片段的模式在对照组和MME -/-动物中是相同的。这些发现表明，在急性PMN介导的炎症模型中，丝氨酸蛋白酶抑制剂和金属蛋白酶抑制剂具有相似的抗炎特性，炎症不是通过产生趋化基质片段的蛋白水解介导的，并且经典的抗蛋白水解（蛋白酶与抗蛋白酶络合）可能不发挥抑制炎症的作用。这些药物的抗蛋白水解作用似乎不是由内源性α - 1AT的保护介导的。
There is increasing evidence that antiproteases are able to affect the inflammatory response. To further examine this question, we administered human ce-l-antitrypsin (al AT) or a synthetic metalloprotease inhibitor (RS113456) to C57 mice followed by a single intratracheal dose of quartz, a dust that evokes a marked, lasting, polymorphonuclear leukocyte (PMN) infiltrate. At 2 hours after dust administration, both antiproteases completely suppressed silica-induced PMN influx into the lung and macrophage inflammatory protein-2 (MIP-2)/monocyte chemotactic protein-1 (MCP-1) (neutrophil/macrophage chemoattractant) gene expression, partially suppressed nuclear transcription factor kappaB (NF-kappaB) translocation, and increased inhibitor of NF-kappaB (I kappaB) levels. By 24 hours, PMN influx and connective tissue breakdown measured as lavage desmosine or hydroxyproline were still at, or close to, control levels after antiprotease treatment, and increases in NF-kappaB translocation and MIP-2/MCP-1 gene expression were variably suppressed. At both time points, neither agent prevented silica-induced increases in amount of whole lung MIP-2 or MCP-1 protein, but both did prevent increases in whole lung intercellular adhesion molecule-1 (ICAM-1) at 24 hours. Inactivating the alpha 1AT by oxidation to the point that it no longer possessed antiproteolytic properties did not affect its ability to suppress inflammation. Both antiproteases also prevented the silica-induced acute inflammatory response in mice with knocked out genes for macrophage metalloelastase (MME -/-), mice that develop inflammation, but not connective tissue breakdown, and the pattern of alpha 1AT breakdown fragments was identical in control and MME -/- animals. These findings suggest that, in this model of acute PMN mediated inflammation, a serine protease inhibitor and a metalloprotease inhibitor have similar anti-inflammatory properties, that inflammation is not mediated by proteolysis with generation of chemotactic matrix fragments, and that classic antiproteolysis (complexing of protease to antiprotease) probably does not play a role in suppression of inflammation. The antiproteolytic effects of these agents do not seem to be mediated by protection of endogenous alpha 1AT.