基质金属蛋白酶在儿科领域的研究进展

基质金属蛋白酶（MMP）是一组结构与功能同源的锌离子依赖性蛋白酶超基因家族，存在于细胞外基质（ECM）中，其主要作用是降解ECM。现将MMP在儿科领域的研究进展情况综述如下。     

基质金属蛋白酶及其抑制因子与肝纤维化

肝纤维化是各种慢性肝病向肝硬化发展的共同病理过程，其实质是以Ⅰ、Ⅲ型胶原为主的细胞外基质（extracellular matrix，ECM）合成与降解失衡，导致ECM在肝内过度沉积。研究表明，基质金属蛋白酶类（matrix metalloproteinases，MMPs）和金属蛋白酶组织抑制因子（tissue inhibitors of metalloproteinases，TIMPs）两者的平衡在ECM的合成与降解中发挥着重要的作用。     

TIMPs和MMPs与肝纤维化研究进展

肝纤维化是多种慢性肝损伤的共同后果,进一步则发展为肝硬化,其特征是细胞外基质（ECM）产生和降解不平衡,导致间质胶原及其它基质成分积聚。近年来,与基质降解与沉积有关的基质金属蛋白酶（MMPS）及其基质金属蛋白酶组织抑制因子（TIMPS）在肝纤维化的发生发展过程中得到较深入研究。基质金属蛋白酶是降解ECM最主要的酶类,而基质金属蛋白酶组织抑制因子为MMPS的特异性抑制剂,二者与肝内ECM的沉积与降解密切相关。MMPS及TIMPS与肝纤维化的关系越来越受到人们的重视。研究发现通过调节TIMPS与MMPS基因的表达来治疗肝纤维化将是肝纤维化基因治疗的新途径。     

基质金属蛋白酶及其组织抑制剂与肿瘤的侵袭和转移

基质金属蛋白酶类（matrix metalloproteinases，MMPs）是降解细胞外基质（extracelluler matrix，ECM）的重要的一组蛋白酶类，其降解ECM的功能在生理上的作用包括伤口愈合、骨吸收、乳腺退化等，在病理生理方面的作用涉及到类风湿性关节炎、冠状动脉疾病及肿瘤等。MMP被认为与肿瘤生长、侵袭、转移有关。许多研究显示肿瘤转移伴有MMPs的过度表达。     

肝纤维化形成中MMPs／TIMPs的动态变化及治疗进展

目前已阐明细胞外基质（ECM）合成与降解失衡,特别是后期降解减少是肝纤维化发生的主要机制。肝脏ECM的代谢主要由基质金属蛋白酶（MMP）及其抑制因子（TIMP）共同调节。MMPs促进ECM降解,而TIMPs通过抑制MMPs阻止ECM降解,从而形成或促进肝纤维化。此外,TIMPs还通过抑制肝纤维化发生、发展过程中具核心作用的肝星状细胞（HSC）凋亡而促进肝纤维化的持续发展。     

慢性乙型肝炎合并糖尿病患者半胱氨酸蛋白酶抑制剂C检测的临床意义

慢性乙型肝炎患者疾病发展过程中,细胞外基质（ECM）的大量沉积是引起肝组织发生病理改变的重要原因,丝氨酸蛋白酶、半胱氨酸蛋白酶、基质金属蛋白酶（MMPs）参与ECM的降解。目前业已证明肝病患者半胱氨酸蛋白酶抑制剂C（CysC）有不同程度的增高。CysC是近年来反映肾小球滤过率新的内源性标志物。     

肝纤维化基质金属蛋白酶-26/基质金属蛋白酶抑制因子-1 mRNA的表达

基质金属蛋白酶（MMPs）是一组能降解细胞外基质（ECM）的酶，该家族的一些酶是迄今为止已发现的惟一能分解纤维类胶原的酶类，MMP-26是MMPs家族的一个新成员，又称endometase或matrilysin-2，MMP-26可能参与一系列与组织重建有关的事件。基质金属蛋白酶组织抑制因子（TIMP）是一组能特异性抑制MMPs活性的低分子蛋白质，     

基质金属蛋白酶-9与慢性阻塞性肺疾病

基质金属蛋白酶(MMPs)是一组具有相同功能、结构高度同源、依赖锌离子的内肽酶的总称,其主要作用是降解细胞外基质(ECM)和基底膜。在正常肺组织中ECM能维持肺泡结构,ECM的合成与降解保持动态平衡,这对于保证正常肺功能非常重要。平衡破坏时,将会产生以肺结构改变为特征的肺泡疾病,如慢性阻塞性肺病(COPD)、支气管哮喘以及特发性肺纤维化(IPF)等。MMP9是MMPs家族的其中一种,它在正常肺组织中的含量很低,但在上述疾病中的含量却很高。MMP9不仅能降解气道和肺的ECM和基底膜,而且能调节其它蛋白酶和细胞因子。研究发现,ECM降解是…     

MMP-2和MMP-9在急性白血病骨髓细胞中的表达及与白血病髓外浸润的相关性

目的：探讨基质金属蛋白酶-2（MMP-2）和基质金属蛋白酶-9（MMP-9）与急性白血病发生和髓外浸润的相关性.方法：采用生物素化鼠抗地高辛标记的原位杂交法检测MMP-2和MMP-9在初治、复发、完全缓解的急性白血病患者和正常对照者的骨髓原代细胞中的表达.结果：MMP-2和MMP-9在初治，特别是有髓外浸润表现者和复发急性白血病骨髓原代细胞中的表达显著高于完全缓解的急性白血病和正常对照者;关于亚型的研究发现，初治急性淋巴细胞白血病组和急性非淋巴细胞白血病（M4＋M5）组中的表达显著高于急非淋（非M4＋M5）组.结论：MMP-2和MMP-9可能通过增强白血病细胞降解细胞外基质（ECM）等机制参与急性白血病的发生和髓外浸润过程，并在其中发挥重要作用。     

COL-Ⅰ、COL-Ⅲ和TIMP-1在实验性肝纤维化中作用的研究进展

肝纤维化是一个动态的、涉及到进展与逆转两方面的病理过程。细胞外基质（ECM）合成增加、降解减少最终导致ECM在肝内的过度沉积是肝纤维化的主要病理改变。ECM的主要成分是I型胶原（COL-Ⅰ）和Ⅲ型胶原（COL-Ⅲ）,基质金属蛋白酶（MMPs）及其抑制物（TIMPs）是调节ECM降解的主要酶,其主要成分MMP-1及其抑制因子（TIMP-1）在抗肝纤维化中发挥了关键作用。本文对近年来COL-Ⅰ、COL-Ⅲ和TIMP-1在实验性肝纤维化中的研究进展进行了综述。     

Targeted deletion of matrix metalloproteinase 2 ameliorates myocardial remodeling in mice with chronic pressure overload

Matrix metalloproteinases (MMPs) play an important role in the extracellular matrix remodeling. Experimental and clinical studies have demonstrated that MMP 2 and 9 are upregulated in the dilated failing hearts and involved in the development and progression of myocardial remodeling. However, little is known about the role of MMPs in mediating adverse myocardial remodeling in response to chronic pressure overload (PO). We, thus, hypothesized that selective disruption of the MMP 2 gene could ameliorate PO-induced cardiac hypertrophy and dysfunction in mice. PO hypertrophy was induced by transverse aortic constriction (TAC) in male MMP 2 knockout (KO) mice (n=10) and sibling wild-type (WT) mice (n=9). At 6 weeks, myocardial MMP 2 zymographic activity was 2.4-fold increased in WT+TAC, and this increase was not observed in KO+TAC, with no significant alterations in other MMPs (MMP 1, 3, 8, and 9) or tissue inhibitors of MMPs (1, 2, 3, and 4). TAC resulted in a significant increase in left ventricular (LV) weight and LV end-diastolic pressure (EDP) with preserved systolic function. KO+TAC mice exerted significantly lower LV weight/body weight (4.2+/-0.2 versus 5.0+/-0.2 mg/g; P<0.01), lung weight/body weight (4.9+/-0.2 versus 6.2+/-0.4 mg/g; P<0.01), and LV end-diastolic pressure (4+/-1 versus 10+/-2 mm Hg; P<0.05) than WT+TAC mice despite comparable aortic pressure. KO+TAC mice had less myocyte hypertrophy (cross-sectional area; 322+/-14 versus 392+/-14 microm2; P<0.01) and interstitial fibrosis (collagen volume fraction; 3.3+/-0.5 versus 8.2+/-1.0%; P<0.01) than WT+TAC mice. MMP 2 plays an important role in PO-induced LV hypertrophy and dysfunction. The inhibition of MMP 2 activation may, therefore, be a useful therapeutic strategy to manage hypertensive heart disease.     

Lymphoid tissue collagen deposition in HIV-infected patients correlates with the imbalance between matrix metalloproteinases and their inhibitors

We studied the lymphoid tissue biopsies of 20 patients with chronic human immunodeficiency virus (HIV) infection by analyzing collagen deposition, CD4+ cell number, and gene expression of metalloproteinases (MMPs; MMP-2, MMP-9) and tissue inhibitors of MMPs (TIMPs; TIMP-1, TIMP-2). HIV-infected patients had significantly increased collagen deposition (P = .001), fewer CD4+ T cells (P = .05), and decreased MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios (P = .01), compared with HIV-negative control patients. Moreover, we found a significant negative correlation between collagen deposition and the MMP-9/TIMP-1 ratio (ρ = -0.50; P = .047). To our knowledge, this is the first time that MMP/TIMP imbalance has been correlated with lymphoid tissue collagen deposition and incomplete immune recovery in HIV-infected patients, even after long-term antiretroviral treatment.     

Matrix metalloproteinases and peripheral arterial disease

Matrix metalloproteinases (MMPs), a family of enzymes that degrade extracellular matrix, are emerging as important modulators of atherothrombosis. MMPs are produced by inflammatory cells; some of them are also released by activated platelets and play a crucial role in the remodeling processes, leading to atherosclerotic plaque formation, plaque rupture, arterial aneurysm development, and critical limb ischemia. Independent from their matrix degrading activity, MMPs also regulate some cell functions relevant to atherothrombosis, such as platelet activation, neutrophil activation, and vascular reactivity. Plasma levels of some MMPs are increasingly being recognized as a biomarker of atherosclerosis and cardiovascular risk. In peripheral arterial disease, MMPs have been shown to be involved in angiogenesis, arteriogenesis, and the development of arterial calcifications. Increased plasma levels of some MMPs (MMP-2, MMP-9) have been correlated with PAD development and severity. Single nucleotide polymorphisms of the genes encoding for some MMPs have also been associated with the risk of developing peripheral arterial disease and critical limb ischemia. Large prospective observational studies are needed to further demonstrate the role of MMPs in PAD. In perspective, pharmacologic targeting of the expression or activity of MMPs may represent a novel, attractive approach for the treatment of peripheral arterial disease.     

Monocyte phenotype as a predictive marker for wound healing in diabetes-related foot ulcers

AimsDelayed healing of diabetes-related foot ulcers (DRFUs) is associated with increased macrophage and matrix metalloproteinases (MMPs) at the wound site. Whether circulating monocyte phenotype and/or MMPs are altered in association with wound healing outcome is unknown, and was investigated in this study.MethodsBlood was obtained from 21 participants with DRFU, at initial visit (V1), week-4 (V2), and week-8 (V3) for measurement of monocyte number (CD14⁺), phenotype (CD16, CD163) and chemokine receptors (CCRs) by flow cytometry, and circulating MMPs and TIMP-1 by ELISA.ResultsSix wounds healed during the study. At V1, non-classical CD16⁺⁺ monocytes and MMP-3 were higher in healed vs unhealed (both p < 0.05). At V3, the increased %CD16⁺⁺ persisted and %CCR2⁺ was decreased in healed, but no other monocyte markers nor MMP/TIMP differed between groups. Increased wound closure rate (WCR) at V3 correlated with increased %CD16⁺⁺ monocytes and decreased MMP-2 at V1 or V1 + V2. Receiver operating characteristic (ROC) curves yielded an area-under-the-curve of %CD16⁺⁺ at V1 of 0.78 to predict ulcer healing at V3.ConclusionsThese results indicate that circulating monocyte phenotype and MMPs alter as DRFUs heal. The relationship of %CD16⁺⁺ monocytes with WCR and ROC curve suggest a predictive role of %CD16⁺⁺ monocytes for ulcer healing.     

Extracellular matrix -- from basic research to clinical significance. An overview with special consideration of matrix metalloproteinases

Matrix metalloproteinases (MMPs) hydrolyze most components of the extracellular matrix (ECM). These proteinases play a central role in many biological processes such as normal tissue remodeling, embryogenesis, wound healing and angiogenesis. Currently about 26 MMP genes have been identified, and most are multidomain zinc endopeptidases. Knowledge of their tertiary structure is crucial for the understanding of the functional properties of MMPs. In healthy tissue a strict regulation of MMPs is critical in order to maintain proper ECM homeostasis. Among other levels of regulation, MMPs are precisely regulated by their main endogenous protein inhibitors (TIMPs). Disruption of this balance results in serious diseases such as fibrosis, arthritis, and tumour growth. Several studies have documented the importance of MMP-mediated ECM destruction for tumour initiation, growth, migration, angiogenesis, invasion and metastasis. Certain MMPs such as gelatinases (MMP-2, MMP-9) have special mechanisms to localize at leading edges in tumour tissue. MMPs can no longer be thought of solely as ECM destructionists, but as part of an elegant communication system through which epithelial and tumor cells interact with the stroma.     

Vascular cell adhesion molecule 1 (VCAM-1) activation of endothelial cell matrix metalloproteinases: role of reactive oxygen species

Lymphocytes bound at endothelial cell junctions extravasate within minutes. Lymphocyte-endothelial cell binding is mediated by receptors such as vascular cell adhesion molecule 1 (VCAM-1). VCAM-1 activates endothelial cell nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in minutes, and this activity is required for VCAM-1-dependent lymphocyte migration. In this report, we examined mechanisms for activation of matrix metalloproteinases (MMPs) during VCAM-1-dependent lymphocyte migration. Lymphocyte binding to VCAM-1 rapidly activated endothelial cell-associated MMPs. Furthermore, inhibition of MMPs on the endothelial cells but not on the lymphocytes blocked VCAM-1-dependent lymphocyte migration across endothelial cells. The activation of endothelial cell MMPs required VCAM-1-stimulated endothelial cell NADPH oxidase activity as determined by scavenging of reactive oxygen species (ROS) and by pharmacologic or antisense inhibition of NADPH oxidase. Exogenous addition of 1 microM H(2)O(2), the level of H(2)O(2) generated by VCAM-1-stimulated endothelial cells, rapidly activated endothelial cell-associated MMPs. In contrast, activation of lymphocyte-associated MMPs was delayed by hours after binding to VCAM-1, and this activation was blocked by inhibition of endothelial cell ROS generation. There was also a delay in H(2)O(2)-induced decrease in lymphocyte-associated tissue inhibitors of metalloproteinases (TIMPs), resulting in an increase in MMP/TIMP ratio. In summary, this is the first report of a mechanism for ROS function in VCAM-1 activation of endothelial cell MMPs during VCAM-1-dependent lymphocyte migration.