MMP-2、MMP-9及其抑制剂TIMP-2、TIMP-1与肾脏疾病

肾脏细胞外基质(ECM)合成与降解失衡及其组织重塑导致的ECM积聚,是各种肾脏疾病发展至肾间质纤维化与肾小球硬化乃至终末期肾衰的共同病理表现.基质金属蛋白酶(MMP)是肾脏ECM降解的关键酶,金属蛋白酶组织抑制因子(TIMP)-2、-1分别为MMP-2、MMP-9内源性抑制剂.在不同类型的肾脏疾病或同一疾病的不同病理发...     

Dysregulated expression of matrix metalloproteinases and their inhibitors may participate in the pathogenesis of pre-eclampsia and fetal growth restriction

Background

Trophoblast invasion into the maternal endometrium serves an important function in human pregnancy. Dysregulation of the finely controlled process of trophoblast invasion can result in a wide spectrum of pregnancy abnormalities.

Aims

We aimed to elucidate the relationship between the expression of matrix metalloproteinases and pregnancy complication.

Study design

The study group consisted of placental bed biopsy tissues obtained from normal vaginal deliveries (N = 15), normal cesarean deliveries (N = 15), pre-eclampsia (N = 24) and fetal growth restriction (FGR) (N = 10). We evaluated the expressions of MMP-2, -8, -9, -11, -19, -15 (MT2-MMP), -16 (MT3-MMP), and -24 (MT5-MMP), as well as TIMP-1 and -3, by applying Western blot and immunohistochemistry methods.

Subjects

Human placental tissues were used for this study.

Outcome measures

The expressions of MMP-2, -8, -9, -11, -19, -15 (MT2-MMP), -16 (MT3-MMP), and -24 (MT5-MMP), as well as TIMP-1 and -3 in human placenta tissues.

Results

Compared with those in normal pregnancies, the expression of MMP-2, -8, -9 and -11 was downregulated in villous tissues of pre-eclampsia and FGR cases (p < 0.05). TIMP-1 and -3 were increased in pre-eclampsia and FGR (p < 0.05). No significant difference was found between normal vaginal deliveries and cesarean deliveries.

Conclusions

We speculate that the change in invasion-associated proteinase expression will affect placental development and may thus contribute to the development of complicated pregnancies.     

基质金属蛋白酶及其组织抑制剂在高氧性肺损伤中的变化

目的 探讨基质金属蛋白酶(MMPs)及其组织抑制剂(TIMPs)在高氧性肺损伤中表达及意义。方法 幼年Wistar大鼠32只,随机分为空气组和高氧组,并于高氧暴露3、7、14 d后用免疫组织化学方法(SABC)观察MMP-2、MMP-9、TIMP-1、TIMP-2在肺组织中的分布,用逆转录聚合酶链反应(RT-PCR)观察MMP-2、MMP-9、TIMP-1、TIMP-2 mRNA在肺组织中表达,此外对支气管肺泡灌洗液(BALF)中的蛋白含量、肺通透系数、肺湿／干重比(W／D)及肺组织病理学改变也进行对比分析。结果 高氧组3 d时肺组织出现水肿、出血、炎性细胞浸润,7 d时进一步加重,14 d时间质细胞增生,肺间隔明显增宽,出现肺纤维化倾向。W／D值、肺通透系数和BALF蛋白含量在3、7、14 d均明显高于空气组(P均<0.05)。免疫组化法示MMP-2、MMP-9、TIMP-1、TIMP-2在正常肺泡上皮细胞、支气管上皮细胞呈弱阳性表达,高氧组3 d时肺泡上皮细胞、支气管上皮细胞、巨噬细胞、肺泡间质细胞均呈强阳性表达,7、14 d表达更广泛。与空气组相比,高氧3 d时MMP-2、MMP-9 mRNA表达水平明显增加,7 d时最显著,14 d开始下降(P均<0.05),而TIMP-1、TIMP-2 mRNA表达却持续增加,14 d时仍无明显下降(P均<0.05)。高氧暴露后MMP-2／TIMP-2、MMP-9／TIMP-1比值亦增加,其中7 d时最为显著,14 d开始下降。结     

MMP-2 and MMP-9 and their tissue inhibitors in the plasma of preterm and term neonates

Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are involved in a variety of physiologic growth and development and pathophysiologic inflammatory conditions. We hypothesized that 1) MMP-2 and -9 plasma activities and TIMP-1 and -2 plasma concentrations in preterm and term neonates were dependent on the gestational and postnatal age; and 2) the respective MMP and their inhibitors were deranged in the development of bronchopulmonary dysplasia (BPD) and intraventricular hemorrhage (IVH) in preterm neonates. From 1998 to 1999, blood samples were collected from preterm neonates (25-36 wk gestation) with or without BPD and/or IVH as well as from healthy term (37-40 wk gestation) neonates during the first 28 d of life. MMP-2 and MMP-9 plasma activities were measured by zymography; TIMP-1 and TIMP-2 plasma concentrations were determined by ELISA. In neonates without BPD or IVH (n = 50), MMP-2 and MMP-9 plasma activities both appeared to be gestational age dependent, with the highest levels observed in neonates of 33-36 wk gestation. TIMP-1 plasma concentration was highest in term neonates but no gestational difference was found in TIMP-2. Only MMP-9 showed a 50% decrease after d 1 in the first postnatal month. Twelve preterm infants with BPD and/or IVH had significantly lower MMP-2 but higher MMP-9 activity and higher TIMP-1 concentration than those of corresponding neonates without BPD or IVH. These findings show the gestational age-dependent expression of plasma MMP activities and their inhibitors. MMP and TIMP may be involved in the feto-neonatal development and may contribute to the pathogenesis of BPD and/or IVH in critically ill preterm neonates.     

Expression of matrix metalloproteinases 2, 7 and 9, and their tissue inhibitors 1 and 2, in developing rabbit tracheae

BACKGROUND: Structural changes in the developing conducting airway impact the rigidity of the airway, altering the airway's ability to sustain its shape during ventilation. The developmental changes in airway compliance oppose the changes in compliance of the developing lung; thus the expression profiles of matrix modeling proteins likely are also opposite in these developing organs. OBJECTIVES: To determine the profiles of matrix metalloproteinases (MMPs) -2, -7, and -9 and tissue inhibitors (TIMPs) -1 and -2 in the developing trachea and test the hypothesis these profiles would contrast those previously reported for the lung. METHODS: Rabbits tracheae were harvested at 21 days of gestation, 3 and 17 days postgestation and at adulthood. Tissue homogenates were analyzed by substrate zymography for the activity of MMPs, and reverse zymography for TIMPs. Immunostainings on neonatal lamb tracheal rings were used to localize MMP-2 and 9. RESULTS: Analysis revealed an age-dependent decrease in total MMP-2 quantity and the ratio of active to latent forms. TIMP-2 shows a time-dependent increase throughout airway development. Total MMP-9 and TIMP-1 quantities were unchanged across these ages, although MMP-9 protein was found predominantly in its latent form during development and predominantly in its active form during adulthood. Respiratory epithelial cells reacted positive for both MMP-2 and 9 and trachealis muscle fibers were positive for MMP-2. No MMP-7 expression was identified in the rabbit airway. CONCLUSIONS: The opposing developmental patterns in MMP-2 expression between the airway and lung lead to speculation regarding the role of MMP-2 activity on changes in organ compliance.     

吸入激素对哮喘大鼠基质金属蛋白酶-9及其抑制剂的表达调控

目的探讨基质金属蛋白酶9(MMP9)及其组织抑制物(TIMP1)在支气管哮喘发病中的作用,评价吸入糖皮质激素对其调节作用。方法建立哮喘大鼠模型,用ELISA、免疫组织化学、westernblot及RTPCR技术,对激素治疗前后哮喘大鼠肺组织中MMP9及TIMP1表达进行研究。结果(1)通过大鼠行为学改变、呼吸功能曲线、IgE水平以及肺组织切片证实哮喘模型成立。(2)哮喘组肺组织细小支气管壁及伴行动脉周围炎性细胞浸润,黏膜断裂,杯状细胞增生,平滑肌增厚;21天组气道壁基膜增厚和平滑肌增生更加明显。(3)大鼠肺组织MMP9mRNA表达:哮喘7天组为(2.71±0.37),21天组为(1.76±0.27),激素治疗组为(0.88±0.18),正常对照组为(0.52±0.10),组间比较差异有统计学意义(F=151.52,P<0.01)。大鼠肺组织TIMP1mRNA表达:哮喘7天组为(1.13±0.19),21天组为(1.55±0.24),激素治疗组为(0.77±0.15),正常对照组为(0.47±0.08),组间比较差异有统计学意义(F=69.46,P<0.01)。(4)免疫组织化学及蛋白质表达结果与RTPCR结果一致。结论从蛋白质水平及mRNA水平证实哮喘大鼠模型肺组织MMP9表达升高,TIMP1表达亦增强;激素下调MMP9及TIMP1表达,可能是其抑制气道炎症和气道重塑的机制之一。     

川崎病患儿血清中hs-CRP与基质金属蛋白酶及抑制剂联合检测的临床意义

目的：检测基质金属蛋白酶(MMP)-2、MMP-9、基质金属蛋白酶抑制剂(TIMP)-1及hs-CRP在川崎病患儿血清中的表达,并探讨其与冠状动脉损伤的关系。方法：选取151例川崎病患儿作为观察组（无冠状动脉损伤40例,有冠状动脉损伤111例）,60例健康儿童作为对照组,采用酶联免疫吸附实验(ELISA)检测血清中MMP-2、MMP-9和TIMP-1含量,应用终点散射比浊法检测血清hs-CRP的含量。结果：MMP-2,MMP-9及hs-CRP含量在冠脉损伤组及无冠脉损伤组与对照组比较差异均有显著性,在冠脉损伤组量最高（P<0.05）;川崎病患儿中MMP-2、MMP-9及TIMP-1之间的检测量呈正相关（P<0.05）。结论：MMP-2、MMP-9、TIMP-1及hs-CRP在川崎病的发生发展中可能起重要作用,MMP-2、MMP-9及hs-CRP的联合检测可能对判断病变程度有重要帮助。［中国当代儿科杂志,2009,11（12）：989-991］     

黄芪皂甙Ⅳ对大鼠心肌成纤维细胞胶原影响

目的探讨黄芪皂甙Ⅳ（XGA）对大鼠心肌成纤维细胞胶原影响及其量效和时效关系。方法采用胶原酶（胰蛋白酶消化法分离大鼠心肌成纤维细胞（FBC）,建立FBC培养系统。在FBC培养系统内加入不同质量浓度和不同作用时间的XGA,提取RNA后用反转录PCR（RT-PCR）法检测Ⅰ、Ⅲ、Ⅳ型胶原,基质金属蛋白酶（MMP-1、-2、-9）及其抑制剂（TIMP-1、-2）mRNA的表达水平。结果予不同水平和不同作用时间XGA后,FBC培养系统RT-PCR产物凝胶电泳显示有Ⅰ、Ⅲ、Ⅳ型胶原,MMP-1、-2、-9、TIMP-1和-2mRNA表达;与予XGA前比较,Ⅰ、Ⅲ、Ⅳ型胶原,TIMP-1、-2mRNA表达水平有所下降,而MMP-1、-2、-9mRNA表达水平有所上升,且随着XGA剂量增加或作用时间延长而渐下降或上升。Ⅰ、Ⅲ、Ⅳ型胶原,TIMP-1、-2mRNA表达水平与XGA的剂量和作用时间呈负相关（r=-0.927~-0.637P=0~0.024）;MMP-1、-2、-9mRNA表达水平与XGA剂量和作用时间呈正相关（r=0.672~0.962P=0~0.034）。结论XGA可减少心肌成纤维细胞胶原形成,其机制可能为抑制胶原的合成、增加胶原降解。     

Levels of matrix metalloproteinase-9 and its inhibitor in guinea pig asthma model following ovalbumin challenge

Our objective was to investigate the role of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and their cellular sources in guinea pig asthma model following ovalbumin (OA) challenge. Twenty guinea pigs were divided into 2 groups: OA-challenged group were sensitized by intraperitoneal injection with OA and exposed to OA while the control group used saline in a similar manner. The positive level index (PLI), defined as the percentage of positive-stained cells × average optical density, was used to assess the expressing levels of MMP-9 and TIMP-1. The levels of MMP-9 from OA-challenged group were significantly higher than those of controls. However, no significant difference of the TIMP-1 levels between the OA-challenged group and controls were found. MMP-9 was expressed strongly in both inflammatory and structural cells while TIMP-1 was expressed weakly in inflammatory cells and structural cells. Our results implied that MMP-9 may contribute to tissue remodeling in asthma and both structural and inflammatory cells within lung tissue are the main cellular sources of MMP-9. Excessive expression of MMP-9 in the early or acute stage of asthma may be associated with the initiation of bronchial injury and inflammatory cells accumulation.     

Hyperoxia decreases matrix metalloproteinase-9 and increases tissue inhibitor of matrix metalloproteinase-1 protein in the newborn rat lung: association with arrested alveolarization

Matrix metalloproteinases (MMP) are likely effectors of normal lung development, especially branching morphogenesis, angiogenesis, and extracellular matrix degradation. Because hyperoxia exposure (>95% O(2)) from d 4 to 14 in newborn rat pups leads to arrest of alveolarization and mimics newborn chronic lung disease, we tested whether hyperoxia altered MMP-2 and -9 mRNA, protein, and enzymatic activity, and the mRNA and protein expression of the endogenous tissue inhibitor of MMP, TIMP-1. No changes due to hyperoxia exposure were observed in MMP-2 mRNA or pro-enzyme (72 kD) protein levels between d 6 and 14, although the overall protein mass and zymographic activity of the active (68 kD) enzyme were diminished (p < 0.05, ANOVA). However, hyperoxia significantly decreased levels of MMP-9 mRNA and pro-MMP-9 protein and diminished overall MMP-9 pro-enzyme activity. TIMP-1 mRNA was not elevated by hyperoxia until d 14, but protein levels were significantly (p < 0.001) elevated by hyperoxia from d 9 to 14. To estimate the potential of MMP inhibition to arrest alveolarization, administration of doxycycline (20 mg/kg, twice daily by gavage), a pan-MMP proteolysis inhibitor, arrested lung alveolarization. We conclude that hyperoxia decreases MMP-9 mRNA, protein, and activity and elevates TIMP-1 protein, and these changes have the potential to contribute to the arrest of normal lung development.     

The role of matrix metalloproteinases -9 and -2 in development of neonatal chronic lung disease

AIM: Matrix metalloproteinases (MMPs) -9 and -2 degrade type-IV collagen, a major constituent of lung basement membrane, and may have a role in the pathogenesis of neonatal chronic lung disease (CLD). We determined factors influencing MMP levels in neonatal bronchoalveolar lavage (BAL) fluid to establish whether an imbalance between MMP and its inhibitor could be implicated in CLD. METHODS: We measured MMP-9 and -2 and tissue inhibitor of metalloproteinase-1 (TIMP-1) levels in 316 BAL fluid samples from 121 babies of gestational ages 23 to 42 wk over the first 14 d of life to determine effects of gestation and postnatal age. Median MMP-9, -2, TIMP-1 and MMP-9/TIMP-1 ratio in BAL were further studied in a subgroup of 85 babies <33 wk gestation to determine their ability to predict CLD and to establish effects of antenatal corticosteroid therapy (ANCS). RESULTS: MMP-9, -2 and TIMP levels did not vary with postnatal age over the first week. Median MMP-9 levels and MMP-9/TIMP-1 ratio increased with decreasing gestation in preterm babies. The MMP-9/TIMP-1 ratio was higher in babies who developed CLD, implying a proteinase/antiproteinase imbalance, but this association disappeared when controlled for gestational age. ANCS had no effect on BAL fluid MMP or TIMP levels. CONCLUSION: MMPs may have a role in the development of lung injury and fibrosis, but estimating their levels in the first week of life does not help with prediction of CLD.     

Expression of matrix metalloproteinases and their inhibitors in retinoblastoma

Tumor invasion is the critical step that could lead to metastasis in retinoblastoma (RB), a common childhood cancer. Matrix metalloproteinases (MMPs) degrade extracellular matrix, which is a crucial step involved in various stages of tumor progression, including tumor angiogenesis, tumor growth, and also local invasion and subsequent distant metastasis. We investigated the role of extracellular MMP inducer (EMMPRIN), MMP-2, MMP-9 and tissue inhibitor of metalloproteinases (TIMPs): TIMP-1, TIMP-2 in RB and correlated clinicopathologically. Among 60 tumors, EMMPRIN was expressed in 40 (64%), MMP-2 in 41 (66%), MMP-9 in 38 (61%), TIMP-1 in 35 (56%), and TIMP-2 in 33 (53%) tumors. EMMPRIN was positive (3+) in 13 (39%) out of 33 tumors with invasion and was positive (3+) in only 1 (3%) out of 29 tumors without invasion. MMP-2 (P<0.0001) and MMP-9 (P<0.0001) were significantly positive (3+) in 7 (21%) and 12 (36%) out of 33 tumors with invasion, whereas positive (3+) in 3 (10%) and faint (1+) in 10 (34%) tumors, respectively, out of 29 tumors without invasion. TIMP-1 (P<0.0001) and TIMP-2 (P=0.04) were significantly positive (3+) in 7 (21%) and 10 (30%), respectively out of 33 tumors with invasion, whereas positive (3+) in only 1 (3%) tumor each out of 29 tumors without invasion. Immunoblotting of tumors confirmed the presence of EMMPRIN, MMPs, and TIMPs. In conclusion, both MMPs and TIMPs may be involved RB invasion and EMMPRIN could play a role in up-regulation of MMP-2 in invasive RB.     

Levels of matrix metalloproteinase-9 and its inhibitor in bronchoalveolar lavage cells of asthmatic children

Our objective was to investigate the role of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) and their cellular sources in childhood asthma. We used 12 controls and 16 asthmatic children. The levels of MMP-9 and TIMP-1 in bronchoalveolar lavage (BAL) cells of asthmatic children were measured immunocytochemically. The positive level index, defined as the percentage of positive-stained cells × average optical density, was used to assess the expressing levels of MMP-9 and TIMP-1. The percentages of eosinophils and mast cells in bronchoalveolar lavage fluid (BALF) of asthmatic children were increased. Levels of MMP-9 and TIMP-1 in BAL cell of asthmatic children were increased significantly at about 30- and 35-fold relative to the controls, respectively. These results suggest that both MMP-9 and TIMP-1 contribute to tissue remodeling. MMP-9, which mediates the degradation of extracellular matrix (ECM), is increased significantly in the early or acute stage and may play a role in ECM degeneration. Excessive TIMP-1 may be synthesized following MMP-9 production when the body tries to repair the damage, which results in excessive deposition of ECM component.     

Expression of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase (TIMP-1) in tissues with a diagnosis of childhood lymphoma

Matrix metalloproteinases (MMP) are enzymes involved in the reconfiguration of the microenvironment by means of degrading the extracellular matrix and have more than 20 subgroups containing zinc. Proteins that serve as the inhibitors of these enzymes are called tissue inhibitors of matrix metalloproteinase (TIMP). These enzymes have been shown to be active in a wide range of processes, from wound recovery to fetus development, heart diseases, and spread of malignant diseases. The aim of this study was to investigate whether there is a relationship between the type, stage, and prognosis of childhood lymphoma subjects and matrix metalloproteinase type-9 (MMP-9) and its inhibitor, tissue inhibitor of matrix metalloproteinase type-1 (TIMP-1). Paraffin blocks of childhood patients diagnosed with non-Hodgkin lymphoma (n = 23), Hodgkin lymphoma (n = 14), or reactive lymphadenopathy (n = 12) were retrospectively immunohistochemically stained with MMP-9 and TIMP-1 stains and whether there was a relationship between the degree of staining and the type, tumor stage, and prognosis of the disease was investigated. Moderate and high degrees of MMP-9 staining were detected in 94.6% of the lymphoma patient tissues and a slight TIMP-1 staining was detected in 21.6% of the lymphoma patient tissues. No relationship was observed between the degree of these staining patterns and the type, tumor stage, and prognosis of the disease. This study indicates that the equilibrium between MMP-9 and TIMP-1 is important in lymphomas in addition to all the physiological and pathologic events although MMP-9 and the TIMP-1 staining patterns are not related to the tumor stage, prognosis, and type of the disease. Larger series of patients are needed to determine the prognostic value of MMP-9 and TIMP-1 in childhood lymphoma.     

颅内出血足月新生儿血清基质金属蛋白酶-9及其抑制剂水平的动态变化

目的探讨颅内出血足月新生儿血清基质金属蛋白酶(MMP)-9、基质金属蛋白酶组织因子(TIMP)-1水平动态变化及其临床意义。方法采用酶联免疫吸附试验法(ELISA)分别测定30例颅内出血患儿在生后1 d内,3、7、15天血清MMP-9、TIMP-1水平及其两者比值,并与30例健康足月新生儿进行对照比较。结果颅内出血足月新生儿血清MMP-9、TIMP-1及MMP-9/TIMP-1水平明显高于对照组(P<0.01),以出生后3 d内MMP-9、TIMP-1水平及MMP-9/TIMP-1最高,7 d后开始下降,随病情恢复其水平缓慢下降,15 d部分患儿恢复正常,但与对照组比较差异仍有统计学意义(P<0.05)。小、中、大量出血患儿血清MMP-9、TIMP-1及MMP-9/TIMP-1与对照组比较,差异均有统计学意义(P<0.01);三组间比较,差异均有统计学意义(P<0.01)。结论颅内出血足月新生儿血清MMP-9、TIMP-1及MMP-9/TIMP-1水平均明显增高,可作为判定病情和评估预后的参考指标。     

Up-regulation of trypsin and mesenchymal MMP-8 during development of hyperoxic lung injury in the rat

Acute lung injury is marked by damage to alveolar-capillary barrier. High pulmonary levels of matrix-degrading serine proteinase trypsin and matrix metalloproteinases (MMP)-2, -8, and -9 have been shown in preterm infants with respiratory distress syndrome (RDS). We studied expression of trypsin and MMP-2, -8, and -9 in rats exposed to >95% oxygen for 24, 48, or 60 h. As demonstrated by zymography and Western immunoblotting, levels of trypsin and MMP-2, -8, and -9 in bronchoalveolar lavage fluid (BALF) sharply increased after 48 h of hyperoxia relative to normoxia controls. This coincided with increase in alveolar-capillary permeability, as indicated by increased protein concentration in BALF. Both neutrophil-derived 80-kD and mesenchymal cell-derived 60-kD MMP-8 isoforms were detected in BALF. Of them, mesenchymal-type MMP-8 predominated. In immunohistochemistry, alveolar epithelium showed strong trypsin expression at 48 and 60 h of hyperoxia, whereas it was predominantly negative in controls. MMP-8 was mostly expressed in macrophages. Marked up-regulation of trypsin and MMP-8 early during hyperoxic lung injury suggests that these enzymes play a role in the pathogenesis of acute lung injury and may therefore be potential targets for therapy of lung injury.     

高氧、维甲酸对早产鼠肺组织基质金属蛋白酶-2、-9 及特异性组织抑制物-1、-2表达的影响

目的探讨基质金属原蛋白-2(MMP-2)、MMP-9、基质金属蛋白酶特异性组织抑制物-1(TIMP-1)和TIMP-2在高氧肺损伤中的作用及维甲酸(RA)的保护作用机制。方法建立高氧(FiO285%)暴露早产SD大鼠肺损伤模型,应用RT-PCR法检测MMP-2、MMP-9、TIMP-1和TIMP-2mRNA表达,采用明胶酶谱检测MMP-2和MMP-9酶原及活酶表达,采用Western blot技术检测TIMP-1和TIMP-2蛋白表达。结果与空气组比较,高氧暴露4、7、14d,MMP-2、MMP-9和TIMP-1 mRNA的表达均显著升高(P均<0.01),MMP-2活酶、MMP-9酶原及活酶和TIMP-1蛋白的表达明显上调(P<0.05);RA对空气暴露下它们的表达均无明显影响(P均>0.05),但不同程度下调高氧暴露后MMP-2、MMP-9、TIMP-1mRNA的表达和MMP-2活酶、MMP-9酶原及活酶的表达,进一步提高TIMP-1蛋白表达;高氧、RA对TIMP-2 mRNA和蛋白的表达均无明显影响(P均>0.05)。结论高氧暴露明显改变MMPs/TIMPs的表达,在肺泡形成关键时期,MMPs/TIMPs之间平衡关系的破坏是造成肺发育受阻和纤维化的重要因素;通过协调MMPs/TIMPs之间的表达,改善肺泡结构,降低肺纤维化程度,从而逆转高氧所致肺损伤,是RA发挥保护作用的重要机制之一。     

全反式维A酸对川崎病患儿急性期单核细胞表达基质金属蛋白酶-9及金属蛋白酶组织抑制剂-1的影响

目的 观察全反式维A酸（atRA）对川崎病（KD）患儿急性期外周血单核细胞表达基质金属蛋白酶-9（MMP-9）和金属蛋白酶组织抑制剂-1（TIMP-1）的影响。方法 分离KD患儿急性期外周血单核细胞（PBMC），分别于不同浓度atRA下培养。采用明胶酶谱法测定其MMP-9活性；酶联免疫吸附法（ELISA）检测其MMP-9和TIMP-1蛋白水平；逆转录PCR（RT-PCR）法检测MMP-9和TIMP-1mRNA表达水平。结果 atRA能在转录水平显著抑制KD患儿急性期单核细胞表达MMP-9和促进TIMP-1表达，引起细胞培养上清MMP-9／TIMP-1蛋白比值和MMP-9活性明显下降（P〈0．01），且在一定浓度范围内，下降趋势与atRA浓度呈正相关。结论 atRA能选择性调节KD患儿急性期单核细胞表达MMP-9和TIMP-1，从而抑制MMP-9活性的过度升高。     

Matrilysins-1 and -2 (MMP-7 and -26) and metalloelastase (MMP-12), unlike MMP-19, are up-regulated in necrotizing enterocolitis

OBJECTIVES: Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of premature infants characterized histologically by extensive tissue injury and inflammation. Matrix metalloproteinases (MMP) are involved in tissue remodeling and cell migration, both being important aspects of inflammatory disease. The aim of this study was to investigate whether MMPs play a role in the pathogenesis of NEC. METHODS: Expression of MMP-1, -7, -9, -10, -12, -19 and -26 was studied using in situ hybridization/immunohistochemistry in samples intestinal tissue removed from 15 patients with NEC; in 7 of them control samples were obtained at closure of stomas. Six intestinal samples from patients with intestinal atresia and four samples of necrosis were also included in the material examined. Laminin-5 was immunostained to find migrating enterocytes and cytokeratin to delineate mucosal epithelium. RESULTS: MMP-7 protein was upregulated in the epithelium of 12/18 NEC samples. MMP-26 was induced in stromal cells of 12/17 NEC specimens. Stromal expression was found for MMP-1 and -12 mRNAs in 7/18 samples. MMP-1 was also detected in the epithelium of regenerating areas. Both NEC and stoma samples expressed MMP-9 in inflammatory cells. Epithelial MMP-19 was downregulated in NEC. CONCLUSIONS: Our results suggest that several MMPs may be major factors in tissue destruction and remodeling in NEC. Targeted inhibition of matrilysins, using synthetic MMP inhibitors or blockers of their signal transduction pathways, may represent a novel therapeutic option for the treatment of intestinal inflammation associated with NEC.