MATRIX METALLOPROTEINASES IN BRAIN INJURY
MATRIX METALLOPROTEINASES IN BRAIN INJURY
复制标题
DOI：
10.1089/neu.1995.12.833
复制
发表时间：
1995-10-01
影响因子：
4.2
通讯作者：
ROSENBERG, GA
中科院分区：
文献类型：
--
作者：
ROSENBERG, GA
细胞外基质的蛋白水解性重塑在关节炎、肿瘤转移、伤口愈合和血管生成的发展和病理过程中正常发生。主要的细胞外基质降解蛋白属于基质金属蛋白酶和纤溶酶原激活物基因家族。脑内注射72 kDa电视胶原酶(明胶酶A)可打开血脑屏障。在出血性脑损伤或脑内注射促炎细胞因子时，内源性产生92 kDa的IV型胶原酶(明胶酶B)。明胶酶B基因含有一个佛波酯反应区，与AP-1蛋白结合，包括早期即时反应基因产物c-Fos/c-jun Diner，损伤时明胶酶B的最大产量出现在16-24小时，使其成为迟效基因。同时还会产生丝氨酸蛋白酶，即尿激酶型纤溶酶原激活物(UPA)，明胶酶和纤溶酶原激活物协同作用，以蛋白水解性方式破坏基底膜。在缺血性和出血性脑损伤后，类似的过程会打开血脑屏障，导致继发性血管源性脑水肿。蛋白水解级联酶的延迟性损伤为治疗提供了机会，时间比人们认为的要晚得多。在第二个治疗窗口中可能的治疗方法包括干扰产生MMPs的基因或抑制基因产物的作用。
Proteolytic remodeling of the extracellular matrix occurs normally during development and pathologically in arthritis, tumor metastasis, wound healing, and angiogenesis. The major extracellular matrix-degrading proteinases belong to the matrix metalloproteinase (MMP) and plasminogen activator gene families. Intracerebral injection of 72-kDa type TV collagenase (gelatinase A) opens the blood-brain barrier. During hemorrhagic brain injury or intracerebral injection of proinflammatory cytokines, endogenous production of 92-kDa type IV collagenase (gelatinase B) occurs. The gelatinase B gene contains a phorbol ester responsive region (TRE) that binds AP-1 proteins, including c-Fos/c-Jun diner, the early immediate response gene products, Maximum production of gelatinase B in injury occurs between 16 and 24 h, making this a late effector gene. The serine proteinase, urokinase-type plasminogen activator (uPA), is also produced at that time, Gelatinases and plasminogen activators work in concert to disrupt basement membranes proteolytically. A similar process opens the blood-brain barrier after ischemic and hemorrhagic brain injury, leading to secondary vasogenic brain edema. Delayed damage by proteolytic cascade enzymes provides opportunities for treatment much later than had been thought possible. Potential treatments possible in this second therapeutic window include interfering with the genes that produce the MMPs or inhibiting the action of the gene products.