血红素加氧酶-1上调自发性高血压大鼠肝脏MMP-2与MMP-9表达

目的 探讨血红素加氧酶-1 (HO-1)对自发性高血压大鼠(SHR)肝脏基质金属蛋白酶-2(MMP-2)与-9 (MMP-9)表达的影响.方法 大鼠随机分为4组:Wistar诱导组(WH)与SHR诱导组(SH)按15 mg/kg每天连续4天腹腔内注射浓度为8 g/L的氯化血红素(hemin)诱导HO-1表达;Wistar对照组(W)与SHR对照组(S)腹腔内注射等体积0.1 mol/L NaOH (pH8.3).检测大鼠尾动脉收缩压.免疫组化法分析肝脏HO-1及MMPs表达.明胶酶谱法检测血浆MMP-2及MMP-9的相对活性.结果 WH组与SH组肝脏HO-1、MMP-2与MMP-9表达量均显著高于W组与S组.HO-1诱导可显著降低SHR大鼠血压.S组血浆MMP-2及MMP-9相对活性显著高于W组.WH组与SH组血浆MMP-2及MMP-9相对活性显著高于W组与S组.结论 HO-1可上调SHR肝脏MMP-2与MMP-9表达.     

低氧抑制猪肺动脉平滑肌细胞MMP-2和MMP-9的表达

目的探讨低氧对猪肺动脉平滑肌细胞（PASMC）分泌基质金属蛋白酶（MMPs）的影响。方法采用酶谱法测定PASMC培养基中MMP-2和MMP-9的酶活性，免疫印迹法检测培养基中MMP-2和MMP-9的蛋白表达，免疫组化法测定细胞原位MMP-2和MMP-9的蛋白表达，RT-PCR法检测mRNA的表达。结果低氧后PASMC分泌的MMP-2酶活性、细胞内外蛋白表达量、mRNA表达量均下降；MMP-9酶活性、细胞外蛋白表达量下降，而细胞内蛋白表达无变化。结论低氧可抑制PASMC分泌MMP-2和MMP-9的酶活性，其机制可能是低氧影响PASMC中MMP-2基因的转录、影响MMP-9蛋白表达后的分泌与活化，导致MMP-2和MMP-9酶活性的改变。     

脑源性神经营养因子对细胞外蛋白水解酶激活作用的研究

 目的：研究脑源性神经营养因子 (BDNF) 对细胞外蛋白水解酶表达和激活作用的影响。 方法：体外分离并培养人脐静脉内皮细胞（HUVEC），RT-PCR法检测HUVEC基质金属蛋白酶MMP-2 、MMP-9 和基质金属蛋白酶组织抑制剂TIMP-1、TIMP-2 mRNA的表达，明胶酶谱检测MMP-2和MMP-9蛋白酶活性，纤维蛋白酶谱检测尿激酶型纤溶酶原激活剂（uPA）蛋白酶活性，Western blotting检测uPA、纤溶酶原激活剂抑制剂（PAI）、TIMP-1及TIMP-2表达。 结果：在对HUVEC增殖无明显促进作用的浓度范围内，BDNF可促进无血清培养的HUVEC MMP-2和MMP-9 mRNA表达,并可促进MMP-2和MMP-9酶原的激活产生活性明胶酶，BDNF对TIMP-1和TIMP-2的表达无明显影响。BDNF以浓度和时间依赖性方式上调HUVEC uPA和PAI-1的表达，并可促进uPA的活性。 结论：BDNF可激活MMPs和uPA/PAI相关的蛋白级联。     

AcSDKP对大鼠心成纤维细胞MMP-2、MMP-9活性和MMP-1表达的影响

目的探讨N-乙酰基-丝氨酰-天门冬酰-赖氨酰-脯氨酸(AcSDKP)对10%血清和血小板源性生长因子(PDGF)诱导的大鼠心成纤维细胞MMP-2、MMP-9活性和MMP-1表达的调节作用。方法明胶酶谱法检测心成纤维细胞MMP-2、MMP-9的活性。Western blot法检测心成纤维细胞MMP-1的表达。结果10%血清和PDGF使心成纤维细胞MMP-2、MMP-9活性增强,也促进MMP-1的表达;AcSDKP能够进一步增加由10%血清和PDGF诱导的心成纤维细胞MMP-2、MMP-9的活性,并促进MMP-1的表达。结论AcSDKP上调了由PDGF介导的心成纤维细胞MMPs活性或表达,这可能与AcSDKP抗心肌纤维化的作用相关。     

中性粒细胞分泌MMP-2和MMP-9发挥促肿瘤作用

目的肿瘤相关中性粒细胞(tumor-associated neutrophils,TANs)分为抗肿瘤的N1型和促肿瘤的N2型,N2型TANs的作用机制尚不清楚。本研究探讨以胃癌细胞培养上清模拟胃癌微环境或用干扰素β抗体抑制细胞干扰素β,能否诱导正常人中性粒细胞分泌基质金属蛋白酶9(matrix metalloproteinase 9,MMP-9)和基质金属蛋白酶2(matrix metalloproteinase 2,MMP-2),影响肿瘤的发生发展。方法收集51例正常人外周血,用中性粒细胞分离液分离中性粒细胞,分别用胃癌MGC-803细胞培养上清干预正常人中性粒细胞;用抗干扰素β(interferon beta,IFN-β)抗体干预正常人中性粒细胞。用Real-time PCR法检测2种干预前后中性粒细胞MMP-9和MMP-2 m RNA的变化,以ELISA法检测2种干预前后中性粒细胞分泌MMP-9和MMP-2的情况,明胶酶谱法检测2种干预前后中性粒细胞分泌的MMP-9和MMP-2的酶活性。结果中性粒细胞在MGC-803上清诱导下,MMP-9和MMP-2 m RNA水平、酶含量和酶活性均增加(P<0.01);中性粒细胞经抗IFN-β抗体干预后,MMP-9和MMP-2 m RNA水平、酶含量和酶活性亦显著高于对照组(P<0.01)。结论胃癌微环境或抑制干扰素β均可使中性粒细胞MMP-9和MMP-2分泌量和酶活性增加,促进肿瘤发展,发挥N2型TANs的作用。     

缺氧对肺动脉成纤维细胞MMP-2、TIMP-1表达的影响

目的：探讨缺氧对肺动脉成纤维细胞（Fpa）分泌基质金属蛋白酶（MMPs）、金属蛋白酶组织抑制剂（TIMPs）的影响。 方法： 采用酶谱法测定Fpa培养基中MMP-2的酶活性，免疫印迹法检测培养基中MMP-2、TIMP-1 的蛋白水平，免疫组化法测定细胞原位的蛋白表达， RT-PCR法检测mRNA表达量。 结果： 缺氧后Fpa分泌的MMP-2酶活性、细胞内外蛋白表达量、mRNA表达量均下降；而TIMP-1的表达则呈相反变化。 结论： 缺氧可使肺动脉成纤维细胞MMP-2/TIMP-1的表达失衡，可能参与缺氧性肺血管重建。     

11-羰基-β-乙酰乳香酸（AKBA）调节基质金属蛋白酶-1,-2,-9的活性(英文)

目的：降低创面的高MMPs活性是治疗慢性皮肤溃疡的新途径。本研究主要观察11-羰基-β-乙酰乳香酸（AKBA,中药乳香的一种活性成分）对MMP-1、MMP-2和MMP-9活性的调节作用。方法： 人间质胶原酶（MMP-1）或者明胶酶A（MMP-2）被醋酸氨基苯汞（p-aminophenylmercuric acetate, APMA)激活后,与不同浓度的AKBA共同孵育1h,通过底物裂解法观察其活性的改变。MMP-9在中性粒细胞（polymorphonuclear neutrophils,PMNs)中含量丰富,因此以大鼠腹腔PMN作为MMP-9的来源。PMN裂解产物与不同浓度的AKBA共同孵育1 h,通过明胶酶谱法观察其中MMP-9活性的改变。我们建立了3个细胞模型：由TNF-α活化的人皮肤成纤维细胞模型;PMA活化的THP-1细胞模型和成纤维细胞-THP-1共培养细胞模型。AKBA与这3个细胞模型共同孵育24 h后,用ELISA法检测细胞上清中MMP-1、MMP-2和MMP-9的含量,用明胶酶谱法检测细胞上清中 MMP-2、MMP-9的活性。结果： AKBA在0.1-0.8 mmol/L浓度范围内对MMP-1、MMP-2的活性有抑制作用,IC50分别为0.18 mmol/L和0.27 mmol/L;在0.05-0.85mmol/L浓度范围内对MMP-9活性表现出不同程度的抑制作用（P<0.01）,其抑制作用呈浓度依赖性。AKBA促进成纤维细胞分泌MMP-2,但是,对THP-1细胞分泌MMP-9表现出抑制作用。在共培养细胞模型中,AKBA对MMP-1、MMP-2和MMP-9的分泌均表现出抑制作用。结论： AKBA作为乳香的一种活性成分,它对MMPs活性的直接抑制作用和对MMPs分泌的抑制作用可能是中药乳香治疗慢性皮肤溃疡的机制之一。     

三氧化二砷对皮肤成纤维细胞、中性粒细胞MMPs活性，TIMP-1及TGF-β1表达的影响

目的:砒石是化腐生肌的常用中药,其主要成分是三氧化二砷(As2O3)。本研究通过观察As2O3对基质金属蛋白酶(MMPs)活性、基质金属蛋白酶组织抑制因子-1(TIMP-1)及转化生长因子β1(TGF-β1)表达影响,探讨化腐中药能否调节胶原代谢,从而治疗慢性皮肤溃疡。方法:明胶酶谱法检测大鼠中性粒细胞(PMNs)来源的MMP-9活性、人成纤维细胞(hFb)分泌的MMP-1、MMP-2的活性,免疫细胞化学法检测hFb TIMP-1、TGF-β1的表达。结果:As2O3浓度在50mg/L时可以提高大鼠PMNs来源的MMP-9的活性(P<0.01);在0.8mg/L可以提高hFb分泌的MMP-1、MMP-2的活性(分别P<0.01);同时As2O3作用于hFb6h、12h、18h后,TIMP-1、TGF-β1表达持续降低(P<0.01)。结论:As2O3在一定范围内可提高PMNs来源的MMP-9的活性;也可提高hFb分泌的MMP-1、MMP-2的活性,同时抑制hFbTIMP-1、TGF-β1的表达。提示砷类制剂可通过提高多种MMPs的活性,降低TIMP-1的表达从而发挥化腐作用。     

太子参对心肌梗死后慢性心衰大鼠心功能与基质金属蛋白酶表达的影响

目的：研究太子参对心肌梗死诱导的慢性心衰大鼠心功能与基质金属蛋白酶（MMPs）表达和活性的作用。方法:采用结扎大鼠冠状动脉复制急性心肌梗死诱导慢性心衰动物模型，以血流动力学指标分析心功能，RT-PCR分析MMP-2与MMP-9的mRNA表达，酶谱法分析MMP-2与MMP-9的活力。结果:大鼠冠脉结扎6周后，心功能显著紊乱；左心室组织MMP-2与MMP-9 mRNA水平显著提高、酶活力增加。太子参水煎液连续灌胃给药5周，可显著改善心衰大鼠的血流动力学，抑制左心室组织MMP-2与MMP-9的活力和mRNA的水平增加（与模型组比较，差异显著，P<0.01，P<0.05）。结论:大鼠冠脉结扎6周形成慢性心衰模型，太子参水煎液可改善大鼠冠脉结扎所诱导的心衰，其机制可能与MMPs的表达和活性有关。     

红景天苷对骨髓抑制贫血小鼠骨髓基质金属蛋白酶的影响

本研究用免疫组织化学方法和酶谱电泳法观察了红景天苷对骨髓抑制贫血小鼠骨髓基质金属蛋白酶-2和-9（MMP-2、MMP-9）的影响，并探讨其在造血调控中的可能作用。免疫组化结果显示，各组小鼠骨髓细胞中均检测到MMP-2和MMP-9表达。与对照组相比，模型组及高、中、低剂量红景天苷组骨髓细胞中MMP-2、MMP-9蛋白表达明显增强。在造模后第4d，中剂量红景天苷组中MMP-2和MMP-9表达最强。在8d，分别是低剂量和中剂量红景天苷组中MMP-2和MMP-9表达最强。酶谱电泳结果显示，在对照组骨髓中可检测到66kD（MMP-2的酶原形式，proMMP-2）、62kD（MMP-2的活性形式，MMP-2）、86kD（MMP-9活性形式，MMP-9）和94kD（MMP-9的酶原形式，proMMP-9）4条明胶酶的活性带，其中MMP-9的活性最强。造模后骨髓造血微环境中明胶酶的活性明显降低，不同剂量的红景天苷均能明显促进proMMP-9和MMP-9的活性增强，使proMMP-2的活性减弱。结果表明，红景天苷可能通过促进骨髓细胞中基质金属蛋白酶表达增强、骨髓造血微环境中基质金属蛋白酶活性升高，进而导致ECM中或基质细胞膜上细胞因子的释放、骨髓微血管损伤的修复以及HSCs增殖、迁移和分化能力的增加来促进骨髓造血功能的恢复。     

Metalloproteinases in juvenile angiofibroma--a collagen rich tumor

Matrix metalloproteinases (MMPs) act in diverse physiological and pathological conditions such as tumor growth and angiogenesis by cleaving extracellular matrix and nonmatrix substrates. MMPs with gelatinase/collagenase activity have not yet been studied in juvenile angiofibroma, a unique fibrovascular tumor with prominent collagen expression. Quantitative real-time polymerase chain reaction studies, Western blot analysis, immunofluorescence studies, gel zymography, and in situ zymography were used to analyze MMP-1, MMP-2, MMP-9, MMP-13, MMP-14, TIMP-1, and TIMP-2 in 9 juvenile angiofibromas and 2 inferior nasal turbinate specimens. Quantitative real-time polymerase chain reaction found significantly elevated expression of MMP-2, MMP-9, and MMP-14 (P < .05) in tumor tissue compared with the inferior nasal turbinate specimens. Western blot analysis detected more prominent MMP-1, MMP-2, and MMP-9 protein levels in juvenile angiofibromas compared with inferior nasal turbinates, but not MMP-13, MMP-14, TIMP-1, and TIMP-2. Immunofluorescent staining proved a mainly stromal localization of the analyzed MMPs. Only MMP-9 and MMP-14 were also detected in vessel walls. MMP-1, MMP-2, and MMP-13 also stained mast cells. Gel zymography indicated increased MMP-2 and MMP-9 gelatinase activity in juvenile angiofibromas compared with inferior nasal turbinates. Finally, in situ zymography detected very high stromal gelatinase/collagenase activity. This study indicates significant expression of MMPs with gelatinase/collagenase activity in juvenile angiofibromas with evidence of a disturbed balance of MMPs to TIMPs toward enhanced MMP activity. These MMPs are assumed to be involved in tumor pathology with an influence on tumor growth and angiogenesis.     

Inhibition of human gelatinases by metals released from dental amalgam.

The interaction between metal ions and the oral environment is a major subject matter in dental research. Matrix metalloproteinases (MMPs) have been implicated in pathologic oral processes such as periodontal tissue destruction, root caries, tumor invasion and temporomandibular joint disorders. The aim of this study was to test the effect of metal ions released from dental amalgam on the major gingival gelatinolytic MMPs. Gingival human explants were cultured overnight in DMEM and the activity of secreted enzymes was analyzed by gelatin zymography in buffers conditioned with dispersed phase or concentional phase dental amalgams. The major enzymes present in conditioned media were characterized as MMP-2 and MMP-9 by immunoprecipitation. The proteolytic activities of MMP-2 and MMP-9 were strongly inhibited by dispersed phase amalgams conditioned buffers. Inhibition of MMP-2 and MMP-9 activities was partly prevented by the addition of 1,10 phenanthroline, a divalent metal chelator, to the amalgam conditioned buffers. Dental amalgam conditioned buffer also inhibited the degradation of denatured type I collagen by purified MMP-2 on liquid phase assays. These findings suggest that the activity of oral tissue MMPs may be modulated by metal ions released from dental amalgam.     

Matrix metalloproteinase-9 in spontaneously hypertensive hyperlipidemic rats.

The presence of hypertension and hyperlipidemia accelerates atherosclerosis and increases the risk of ocular disease. Since there were few rat models for atherosclerosis, spontaneously hypertensive rats (SHRs) and spontaneously hyperlipidemic rats (HLRs) were crossbred to obtain a new model: the spontaneously hypertensive hyperlipidemic rat (SHHR). Matrix metalloproteinases (MMPs) play an important role in ocular degeneration. The purpose of this study is to investigate changes in the MMP activities in vitreous and plasma as well as MMP expression in the retinas of SHHRs, which served as a model of vascular degeneration. We used 8-month-old Wistar-Kyoto (WKY) rats and Sprague-Dawley (SD) rats, SHRs, HLRs, and SHHRs. The MMP-2 and MMP-9 activities in plasma and vitreous were examined by zymography. The mRNA expression of MMP-2, MMP-9, and tissue inhibitor of metalloproteinases-3 (TIMP-3) in retina was examined by quantitative PCR. The localized expression of MMP-9 in the retinas was examined by immunostaining. The MMP-9 activity increased significantly in SHHRs compared with all other rats. MMP-9 was observed mainly at the superficial layer of the retina on immunostaining. The MMP-2, MMP-9, and TIMP-3 mRNA in retina was not significantly different in SHHRs as compared with all other rats. Increased MMP-9 activity in vitreous was influenced more intensely from plasma than retina because there was no change in MMP-9 expression in retina, and MMP-9 immunostaining was observed mainly at the surface of the retina, where blood vessels are present. In this study, the complications of hypertension and hyperlipidemia induced increased MMP-9 activity in vitreous and plasma. It is therefore suggested that MMP-9 may be involved in causing this result and in the development of retinal disease.     

Characterisation of matrix metalloproteinases and the effects of a broad-spectrum inhibitor (BB-1101) in peripheral nerve regeneration

The effect of treatment with a broad-spectrum inhibitor (BB1101) of the matrix metalloproteinases (MMPs) on nerve regeneration and functional recovery after nerve crush was examined. Drug treatment had no effect on latency but from 63 days the compound muscle action potential was significantly increased and was no different to that in the sham-operated controls at 72 days. Levels of MMP mRNA expression, and the localisation and activity of MMP proteins, were examined in rats for a 2 month period following a nerve crush injury, and compared with sham-operated controls. The mRNA of all the MMPs studied was up-regulated by 5-10 days after nerve crush, and they remained up-regulated for 40-63 days, except for MMP-9 which was down-regulated by 10 days. MMP immunoreactivity was localised to Schwann cells, macrophages and endothelial cells, and with the exception of membrane type 1-MMP (MT1-MMP), it was more intense after nerve crush compared with sham-operated controls. Regenerating axons showed immunoreactivity for MMP-2 and MMP-3. In situ zymography confirmed that the activity of MMPs in the nerve was increased following crush but that the activity was greatly reduced in rats treated with BB-1101. Thus despite the inhibition of MMPs by BB-1101, the drug did not appear to essentially affect nerve degeneration or regeneration following nerve crush but that it could be beneficial in promoting the more effective reinnervation of muscles possibly by actions at the level of the muscles.     

Brain regional and cellular localization of gelatinase activity in rat that have undergone transient middle cerebral artery occlusion

Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of ischemic stroke. In particular, the gelatinases MMP-2 and MMP-9 contribute to disruption of the blood-brain barrier and hemorrhagic transformation following ischemic injury. In addition to extracellular matrix degradation, MMPs may directly regulate neuronal cell death through mechanisms that are not completely understood. Here we describe the spatio-temporal distribution of activated MMP-2 and MMP-9 in the brain of rats subjected to 2 h middle cerebral artery occlusion (MCAo) followed by different periods of reperfusion (15 min, 2 h, 6 h and 22 h). By in situ zymography we have observed that gelatinases become activated 15 min and 2 h after the beginning of reperfusion in the ischemic core and penumbra, respectively. In situ zymography signal broadly co-localized with NeuN-positive cells, thus suggesting that proteolysis mainly occurs in neurons. Gelatinolytic activity was mainly detected in cell nuclei, marginally appearing in the cytosol only at later stages following the insult; we did not detect variations in gelatinolysis in the extracellular matrix. Finally, we report that pharmacological inhibition of MMPs by N-[(2R)-2-(hydroxamidocarbonyl-methyl)-4-methylpenthanoyl]-L-tryptophan methylamide (GM6001) significantly reduces brain infarct volume induced by transient MCAo. Taken together our data underscore the crucial role of gelatinases during the early stages of reperfusion and further extend previous observations documenting the detrimental role of these enzymes in the pathophysiology of brain ischemia.     

MMP-9 activity is increased by adiponectin in primary human hepatocytes but even negatively correlates with serum adiponectin in a rodent model of non-alcoholic steatohepatitis

Adiponectin protects from inflammation and fibrosis in metabolic liver disease. In the present study we analyzed whether this adipokine may directly affect the activity of matrix metalloproteinases (MMPs), central regulators of fibrinolysis, in hepatocytes. Global gene expression analysis indicated upregulation of MMP-9 and tissue inhibitor of metalloproteinases-1 (TIMP-1) expression in primary human hepatocytes (PHH) in response to stimulation with adiponectin, and these results were confirmed by real-time RT-PCR. Furthermore, gelatin zymography revealed that MMP-9 activity was significantly induced in supernatants of adiponectin stimulated PHHs. In a murine model of hepatic steatosis and in human steatotic liver samples hepatic MMP-9 activity was not significantly altered. However, in two different murine models of non-alcoholic steatohepatitis (NASH) MMP-9 activity was significantly elevated compared to chow fed control mice. Of note, MMP-9 activity did not or even negatively, respectively, correlate with adiponectin serum levels in these models.The current data indicate that in NASH hepatic inflammation and fibrosis but not hepatic steatosis induce liver MMP-9 activity, and this induction seems to be related to the anti-inflammatory activity of adiponectin rather than its effect on hepatocellular MMP-9 expression.     

Metalloproteinase and cytokine production by THP-1 macrophages following exposure to chitosan-DNA nanoparticles

The use of nanoparticles for gene therapy is gaining more and more interest for medical applications. Chitosan is among the candidate polymers that have a potential application as a gene delivery system. Before using chitosan-DNA nanoparticles in vivo, one must study their interaction and cell's behavior. Since macrophages play an important role in inflammatory processes, this study was performed to investigate the effects of chitosan-DNA nanoparticles on human THP-1 cell line. Cytokine (TNF-alpha, IL-1beta, IL-6 and IL-10) and metalloproteinase (MMP-2 and MMP-9) release as well as their inhibitors (TIMP-1 and TIMP-2) were assessed after time course incubation with different amount of nanoparticles. Their secretion was quantified by enzyme-linked immunosorbent assay. Gelatinolytic activity of MMP-2 and MMP-9 was determined by zymography in cell supernatants and lysates. Cytokine secretion was not detected even in the presence of high amount of nanoparticles. On the contrary, the secretion of MMP-9 in cell supernatants increased significantly after 24 and 48 h in comparison with non-treated cells. MMP-2 secretion was augmented only after 48 h for the highest concentrations of nanoparticles (10 and 20 microg/ml DNA content). However, zymography studies showed that the secreted MMPs were in the proactive forms, while the active form of MMP-9, but not MMP-2, was detected in cell lysates when 10 and 20 microg/ml DNA containing nanoparticles were used. In conclusion, exposure of THP-1 macrophages to Ch-DNA nanoparticles did not induce release of proinflammatory cytokines. The presence of active MMP-9 within the macrophages could possibly be related to nanoparticle phagocytosis and degradation rather than to inflammatory reactions.     

Increased expression of matrix metalloproteinases in the murine zymosan-induced multiple organ dysfunction syndrome

Matrix metalloproteinases (MMPs) have been implicated as mediators of tissue damage in several inflammatory diseases. Since the multiple organ dysfunction syndrome (MODS) is thought to result from systemic inflammation, overactivation of MMPs could contribute to the organ damage observed. The expression and activity of several MMPs were studied in a murine model for MODS. Sixty mice were given an aseptic intraperitoneal injection of lipopolysaccharide, followed, after 6 days, by zymosan. At days 2, 5, 8, 12, and 16 after the injection of zymosan, the liver, lungs, spleen, and kidneys were collected from groups of mice for either RNA extraction, gelatinase zymography and collagenase (MMP-1 and -13) assays (six mice per time point), or immunohistochemistry (three mice per time point). A group of nine mice did not receive zymosan and acted as controls. The expression of MMP-2 mRNA in zymosan-treated mice was strongly up-regulated in liver tissue only. For MMP-9, this was the case in all organs examined. Quantitative gelatin zymography demonstrated the near complete absence of any gelatinase activity in tissues from control mice. However, in the liver, lungs, and especially the spleen of zymosan-treated animals, significantly increased activity of proform and active MMP-2 and -9 was observed with time. Overall, MMP-1 and -13 activities were very low in all samples from the liver and lungs. In the spleen, however, high levels of MMP-1 and -13 were observed in zymosan-treated animals. Immunohistochemical staining for MMP-2 was detected in the liver and spleen, but not in lung and kidney tissue of zymosan-treated animals. Staining for MMP-9 could be detected in liver, lung, and spleen tissues of zymosan-treated mice. For both MMPs, staining appeared to be limited to phagocytes. In conclusion, the data suggest a role for MMPs, especially MMP-9, in the pathogenesis of MODS.     

Experimental metastasis is suppressed in MMP-9-deficient mice

Matrix metalloproteinases (MMPs) are thought to play a key role in tumor invasion and metastasis. The role of MMP-9 (gelatinase B) in tumor metastasis was examined in MMP-9-deficient mice produced by gene targeting using embryonic stem cells. MMP-9-deficient mice develop normally and are fertile. In these mice, the number of metastatic colonies of B16-BL6 melanoma cells or Lewis lung carcinoma cells that were implanted intravenously fell by 45% for B16-BL6 melanoma and 59% for Lewis lung carcinoma (p=0.03 and p=0.0043, respectively). Gelatin zymography showed that both tumor cell lines did not secrete MMP-9 by themselves but the host cells surrounding the tumor cells secrete MMP-9 in vivo. These results indicated that host-derived MMP-9 plays an important role in the process of tumor metastasis.