Matrix metalloproteinase-9 expression in asthma: effect of asthma severity,allergen challenge,and inhaled corticosteroids

BACKGROUND: Asthma is associated with remodeling of the extracellular matrix (ECM) and increased airway obstruction, and the mechanisms of this process are unknown. Matrix metalloproteinases (MMPs) are a group of enzymes capable of degrading the ECM. They are released along with their inhibitors, tissue inhibitor of MMP (TIMP). STUDY OBJECTIVE:s: To determine whether severe, persistent asthma is associated with increased levels of MMP-9 in the airway compared with mild asthma, and to assess the effect of both allergen exposure and steroid treatment on MMP-9 and TIMP-1 levels. DESIGN: Prospective analysis of levels and activity of MMP-9 and TIMP-1 in BAL fluid (BALF) and induced sputum obtained from asthmatics of differing disease severity. In patients with mild asthma, MMP-9 and TIMP-1 levels were studied in induced sputum following allergen challenge and in BALF after inhaled steroid therapy. PATIENTS: Eighteen patients with mild asthma, 10 patients with severe asthma, and 10 nonsmoking, atopic subjects had their sputum studied. Fourteen of the patients with mild asthma underwent allergen challenge. BAL was collected from 16 patients with mild asthma before and after 4 weeks treatment with inhaled budesonide, 800 micro g bid, or placebo. RESULTS: Patients with severe asthma had increased levels and activity of sputum MMP-9 in their sputum compared with patients with mild asthma and normal subjects. Allergen challenge increased the MMP-9/TIMP-1 ratio and MMP-9 activity. Inhaled budesonide had no effect on MMP-9 or TIMP-1 in patients with mild asthma. CONCLUSIONS: MMP-9 may play a role in chronic airway inflammation and remodeling in asthma, as concentrations are increased in severe, persistent asthma and following allergen challenge. Inhaled steroids may not affect MMP-9 and TIMP in patients with mild asthma, and additional studies in patients with more severe asthma are needed.     

Metalloproteinase-9 in induced sputum correlates with the severity of the late allergen-induced asthmatic response

BACKGROUND: Asthma is characterized by airway inflammation and remodeling in which matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMP) play an important role. Allergen exposure activates the inflammatory/repair process in sensitized subjects. Induced-sputum analysis is a non-invasive method that allows the assessment of changes in inflammatory and remodeling mediators implicated in asthma. OBJECTIVES: To evaluate the changes in MMP-9 and its principal inhibitor (TIMP-1) in sputum and plasma of mild allergic asthmatic subjects after whole-lung allergen challenge. METHODS: Induced sputum and blood samples were obtained at baseline, and 6 and 24 h after challenge. MMP-9 and TIMP-1 levels in sputum and plasma were measured by ELISA. RESULTS: Allergen challenge increased the percentage of sputum eosinophils and MMP-9 levels 6 and 24 h after the challenge compared to baseline levels, but TIMP-1 levels did not vary significantly. A significant correlation was observed between MMP-9 levels at 6 h and the maximum percent fall in FEV(1) during the late response. Throughout the study, MMP-9 levels correlated significantly with the number of neutrophils in sputum. CONCLUSIONS: This study shows that analysis of induced sputum is a useful tool to study the variations in MMP-9 and TIMP-1 levels following allergen challenge, therefore allowing to evaluate their role in allergen-induced airway damage and repair.     

Roflumilast, a phosphodiesterase 4 inhibitor, reduces airway hyperresponsiveness after allergen challenge

BACKGROUND: Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, is currently in clinical development for the treatment of asthma. OBJECTIVES: This pilot study examined the effect of roflumilast on allergen-induced airway hyperresponsiveness (AHR) to histamine challenge and asthmatic response to allergen challenge. METHODS: In a randomized, double-blind, 2-period, crossover trial, 13 patients with mild allergic asthma [mean forced expiratory volume in 1 s (FEV(1)) % predicted = 86%] received a single dose of oral roflumilast 1,000 microg or placebo. Patients were administered roflumilast 60 min before allergen challenge, and asthmatic responses were assessed via change in FEV(1) 相似文献   

COPD患者血浆金属蛋白激酶及组织抑制物含量的研究

目的研究慢性阻塞性肺病（Chronic obstructive pulmonary disease,COPD）患者血清基质金属蛋白酶（Matrix metal-loproteinase,MMP）-9和金属蛋白激酶组织抑制物（Tissue inhibitors of metalloproteinases,TIMPs）-1含量,以探讨它们与气道阻塞之间的关系。方法收集72例COPD,26例支气管哮喘（简称哮喘）以及66例对照患者的静脉血,利用ELISA方法测定上述血清TIMP-1和MMP-9含量,并对COPD进行呼吸功能测定,对TIMP-1、MMP-9含量与第一秒用力肺活量进行相关性分析。结果COPD患者血清TIMP-1含量（193.0±5.3μγ/L）显著高于对照组（119.9±6.5）μg/L和哮喘组（162.1±13.6）μg/L,并与COPD患者的第一秒用力肺活量呈负相关性,MMP-9/TIMP-1摩尔比值低于对照组,COPD急性加重期TIMP-1含量升高。结论血清TIMP-1含量在COPD气道阻塞和急性加重期升高。     

Bimosiamose, an inhaled small-molecule pan-selectin antagonist, attenuates late asthmatic reactions following allergen challenge in mild asthmatics: a randomized, double-blind, placebo-controlled clinical cross-over-trial

BACKGROUND: Asthma is characterized by increased recruitment of inflammatory cells from the circulation into the airways. As selectins mediate tethering and rolling of leukocytes on the vascular endothelium, they constitute a promising target for the therapeutic modulation of inflammation. We evaluated the effect of inhaled bimosiamose (TBC1269), a synthetic pan-selectin antagonist, on allergen-induced late asthmatic reactions (LAR) in mild asthmatics. METHODS: Twelve male subjects with mild allergic asthma (only beta-agonists prn) with demonstrable LAR (fall of FEV1 3-8h after allergen inhalation >15% of baseline) at screening completed a randomized, double-blind, placebo-controlled clinical cross-over-trial. Subjects were treated with inhaled bimosiamose 70 mg bid or matching placebo on days 1-3 and 70 mg once on the morning of day 4. On day 4 following the last inhalation of study drug, an allergen challenge was performed. The primary endpoint was the maximum fall in FEV1 between 3 and 8h after allergen inhalation on active treatment vs. placebo. Secondary endpoints included early asthmatic response, exhaled nitric oxide, and airway hyperresponsiveness to methacholine 24h post allergen. RESULTS: Bimosiamose significantly attenuated the maximum LAR compared to placebo by 50.2% (placebo mean+/-SEM fall -13.10+/-2.30%, bimosiamose -6.52+/-3.86%, treatment effect p=0.045; linear mixed-effects model). There was no effect of active treatment on early asthmatic response, post allergen airway hyperresponsiveness or exhaled nitric oxide, and peripheral blood cells. CONCLUSIONS: Administration of the pan-selectin antagonist bimosiamose is effective in a human allergen challenge model of asthma. The result of this proof-of-concept exploratory trial is the first study that demonstrates clinical efficacy of selectin-antagonists as novel therapeutic strategy in asthma.     

Tissue inhibitor of metalloproteinase-1 levels in bronchoalveolar lavage fluid from asthmatic subjects.

Airway remodeling is a well-recognized feature in patients with chronic asthma. The accumulation in the submucosa of fibrous proteins that are substrates of matrix metalloproteinases (MMP), and the demonstration of increased levels of MMP-9 in bronchoalveolar lavage fluid, prompted us to determine whether there was an imbalance between MMPs and tissue inhibitors of metalloproteinase (TIMP) in such patients. We investigated the presence of TIMPs and other MMPs. TIMP levels were compared with those of all MMPs and inflammatory cytokines. Adults with stable asthma, either untreated or treated with glucocorticoids (GCs), were enrolled. Healthy nonsmokers served as a control population. MMPs and TIMPs were identified through zymography or immunoblotting. TIMPs, MMPs, and cytokines were measured with enzyme immunoassays. TIMP-1 levels were significantly higher in untreated asthmatic subjects than in GC-treated subjects or controls (p < 0.0001), and were far greater than those of MMP-1, MMP-2, MMP-3, and MMP-9 combined. TIMP-2 was undetectable. TIMP-1 levels were correlated with levels of interleukin-6 (p < 0.012) and the number of alveolar macrophages recovered (p < 0.005). This observation has important implications, since an excess of TIMP-1 could lead to airway fibrosis, a hallmark of airway remodelling in patients with chronic asthma.     

基质金属蛋白酶-9及其抑制剂在重度慢性阻塞性肺疾病急性加重期的变化

目的探讨基质金属蛋白酶母（MMP-9）及其抑制剂-1（TIMP-1）在重度慢性阻塞性肺疾病急性加重期（AECOPD）的变化及其临床意义。方法应用酶联免疫吸附试验（ELISA）检测35例健康者（对照组）、40例COPD稳定期和急性加重期患者的血清MMP-9和T1MP-1水平,并分析其与肺功能的关系。结果稳定期COPD组MMP-9高于对照组,但两组MMP-9比较差异无统计学意义（P〉0．05）,TIMP-1、MMP-9／TIMP-1均高于对照组（P均〈0．05）;AECOPD组的血清MMP-9、TIMP-1、MMP-9／TIMP-1均高于对照组（分别为P〈0．01,P〈0．05,P〈0．05）;与稳定期比较,AECOPD组MMP-9、TIMP-1、MMP-9／TIMP-1升高（均P〈0．05）;AECOPD组血清MMP-9、TIMP-1、MMP-9／TIMP-1与FEV。％占正常预计值均呈负相关（P均〈0．05）,与稳定期组比较,AECOPD组FEV1、FEV1％占正常预计值有明显下降（P均〈0．05）。结论AECOPD患者血清MMP-9、TIMP-1和MMP-9／TIMP-1比值增加,均与FEV,％占正常预计值呈负相关;MMP-9／TIMP-1比例失衡,可能是导致重度AECOPD肺功能下降的机制之一。     

Sputum matrix metalloproteinase-9, tissue inhibitor of metalloprotinease-1, and their molar ratio in patients with chronic obstructive pulmonary disease,idiopathic pulmonary fibrosis and healthy subjects

BACKGROUND: Matrix-metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), are involved in the turnover of extracellular matrix. Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are inflammatory diseases characterized by excessive matrix degradation and tissue fibrosis. We have compared sputum concentrations of MMP-9, TIMP-1 and the controlling cytokine tumor necrosis factor (TNF)-alpha in patients with COPD, IPF and healthy subjects. METHODS: In a cross-sectional analysis, 12 patients with stable COPD, 15 patients with IPF and 14 healthy subjects underwent sputum induction. Induced sputum cells were counted and concentrations of MMP-9, TIMP-1 and TNF were measured by enzyme immunoassays. RESULTS: Sputum neutrophils were markedly elevated in COPD and IPF patients compared with controls (P<0.001, both comparisons). Concentrations of MMP-9 and the MMP-9:TIMP-1 ratio were increased in COPD (P<0.001 vs. IPF and controls), whereas sputum TIMP-1 levels were both elevated in COPD and IPF (P<0.01 vs. controls, both comparisons). TNF levels were similar in all three groups (P>0.2, all comparisons). MMP-9 concentrations were negatively correlated with airway obstruction (FEV1 FVC) in COPD (rho=-0.62, P=0.03), but not with diffusion capacity or vital capacity (% predicted) in IPF (rho=-0.06, P=0.85, and rho=-0.3, P=0.29, respectively). MMP-9 was positively correlated with sputum neutrophils in all patients (rho=0.68, P<0.0001), and with TNF in COPD patients (rho=0.76, P=0.004). CONCLUSIONS: These data underline the significance of protease/antiprotease imbalance for the pathogenesis of inflammatory lung diseases. Despite similar cellular inflammatory patterns both in COPD and IPF sputa, marked differences were observed with regard to MMP-9:TIMP-1 balance.     

Induced sputum matrix metalloproteinase-9 correlates with lung function and airway inflammation in children with cystic fibrosis

Matrix metalloproteinases (MMPs) degrade extracellular matrix and are implicated in causing airway damage in chronic inflammatory lung diseases, including cystic fibrosis (CF). Our primary objective was to examine the relationship between matrix metalloproteinase-9 (MMP-9) and pulmonary function, as measured by forced expiratory volume in 1 sec (FEV1), in children with CF. We measured MMP-9 and its natural tissue inhibitor of metalloproteinase-1 (TIMP-1) in induced sputum from 18 clinically stable CF children with normal to mildly abnormal lung function and 7 healthy control children. Measures of airway inflammation from induced sputum included cell counts and differentials, interleukin-8 (IL-8), neutrophil elastase, MMP-9, and TIMP-1. Infection was assessed through quantitative bacterial counts. Induced sputum levels of MMP-9 and TIMP-1 were significantly increased in children with CF compared with healthy controls. Also, the MMP-9/TIMP-1 molar ratio was higher in the CF group. Among CF children, there was a significant inverse relationship between MMP-9 and FEV1. In addition, sputum MMP-9 and TIMP-1 concentrations significantly correlated with total white cells and neutrophils, IL-8, and neutrophil elastase. Neither MMP-9 nor TIMP-1 correlated with airway infection. We conclude that clinically stable CF children with normal to mildly abnormal lung function have an increased burden of MMP-9 in their airways. The observed relationships of MMP-9 with lung function and other measures of airway inflammation suggest that this enzyme may be a useful marker of airway injury and airflow obstruction in persons with CF.     

Increased numbers of both airway basophils and mast cells in sputum after allergen inhalation challenge of atopic asthmatics

Mast cells and basophils are metachromatic cells that participate in allergic inflammation. Allergen challenge to the airways of atopic asthmatic individuals increases levels of metachromatic cells, which may reflect an increase in mast cells, basophils, or both. We conducted a study to characterize the kinetics of basophil and mast cell recruitment to the airways of atopic asthmatic subjects after allergen inhalation challenge, using monoclonal antibodies specific for each type of cell. Of 19 subjects, 14 developed both early- and late-phase asthmatic responses (dual responders [DRs]), whereas five developed only early asthmatic responses (early responders [ERs]) after allergen inhalation. There was a significant increase in the number of sputum eosinophils (p < 0.002) and basophils (p < 0.002) at 7 h and 24 h after challenge in both ERs and DRs. There was also a significant increase in the number of activated eosinophils (p = 0. 00002) and mast cells (p = 0.009) in sputum at 7 h and 24 h after challenge in DRs, but not in ERs (p > 0.4). DRs had a significantly higher number of allergen-induced sputum basophils than did ERs (p < 0.01), and sputum basophils correlated significantly with airway hyperresponsiveness (AHR) to methacholine at 24 h after challenge (r = 0.66, p = 0.002). DRs tended to have higher allergen-induced basophil levels than did ERs, which may contribute to the observed AHR.     

MMP-9 and TIMP-1 levels in the sputum of patients with chronic obstructive pulmonary disease and asthma

Chronic obstructive pulmonary disease (COPD) and asthma are associated with morphological changes in airway and lung and metalloproteinases are tought to play a role in this destruction. The aim of this study is to compare the levels of matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinases (TIMP)-1 in the airways of COPD and asthma patients in stable period. We measured MMP-9 and TIMP-1 levels in the induced sputum of 20 asthma, 22 COPD patients in stable period and 15 healthy controls. MMP-9 and TIMP-1 levels were measured by using ELISA kits. MMP-9 and TIMP-1 levels were higher in patient groups than the controls. In COPD patients MMP-9 and TIMP-1 were significantly higher than the controls (respectively; p= 0.0001, p= 0.0001). Similarly, in asthma patients MMP-9 and TIMP-1 levels were higher than the controls (respectively; p= 0.005, p= 0.002). However, while there were no significant difference in MMP-9 levels between the patient groups (p= 0.29), TIMP-1 levels were significantly higher in COPD patients (96.2 +/- 58.2 versus 52.8 +/- 52 microg/mg protein, respectively, p= 0.0001). Atopic asthma patients TIMP-1 levels were slightly higher than non-atopic asthma patients (p> 0.05). There was no significant correlation between FEV(1) and MMP-9 or TIMP-1 levels in all groups. Although known pathogenetic differences in COPD and asthma, the increases in protease-antiprotease levels in both two patient groups may be associated with bronchial and parenchimal morphological changes. New treatment strategies which are focused on modulating of increased protease-antiprotease levels may be give a hope to patients with COPD and asthma.     

综合方法评估药物干预对支气管哮喘的控制

目的从哮喘控制测试（asthma control test,ACT）评分、高分辨CT、肺功能及病理学等方面综合探讨药物干预对哮喘控制的影响。方法筛选哮喘患者48例于稳定期行HRCT、肺功能及留取痰液,根据GINA方案规范化分级治疗1年后再次随访,行ACT评分,并再次行上述检查,利用酶联免疫吸附试验（enzyme linked immunosorbent assay,ELISA）方法检测痰液中基质金属蛋白酶-9（matrix metalloproteinase-9,MMP-9）、基质金属蛋白酶抑制剂-1（tissue-inhibitor metalloproteinase,TIMP-1）、转化生长因子β1（transforming growth factor-β1,TGF-β1）的水平,并行痰涂片计数嗜酸粒细胞（EOS）百分比。结果①规律的药物治疗后,有34例患者进入实验组,进行1年来ACT评估：完全控制组15例,部分控制组12例,未控制组7例;各组间WA%、2T/D比较,完全控制组与部分控制组相比有统计学意义（P〈0.05）,TGF-β1在完全控制组与部分控制组、未控制组比较有统计学意义（P〈0.05）;②哮喘患者治疗后高分辨CT的2T/D、WA%、吸呼气相CT差值、MMP-9、TIMP-1、TGF-β1浓度较治疗前比较有统计学意义,呈降低趋势（P〈0.01）;③治疗后患者2T/D、WA%与MMP-9、TIMP-1、MMP-9/TIMP-1及TGF-β1呈正相关（P〈0.05）,而与FEV1%pred、FEV1/FVC%、FVC%pred呈负相关（P〈0.05）;且EOS%与FEV1%pred、FEV1/FVC%呈负相关（P〈0.05）。结论①ACT评分、高分辨CT、肺功能及痰液检测等可综合全面的评价哮喘的控制情况;②药物干预治疗可使哮喘患者的气道壁厚度、气体潴留、肺功能得到改善,并使炎症细胞因子有所下降,从而阻止哮喘的反复发作及不可逆气流阻塞的形成。     

Matrix metalloproteinase-9 and tissue inhibitor metalloproteinase-1 levels in essential hypertension. Relationship to left ventricular mass and anti-hypertensive therapy

To test the hypothesis that the activity of enzymes degrading the extracellular matrix in hypertensive patients are abnormal, and that the treatment of hypertension will normalise these abnormalities, we measured the serum levels of metalloproteinase MMP-9, and its inhibitor, tissue metalloproteinase inhibitor (TIMP-1). Thirty-two patients with untreated hypertension (BP 168/96) had significantly lower levels of both MMP-9 and TIMP-1 when compared to 24 matched normotensive controls (BP 123/80) (P<0.001). There was no significant correlation between MMP-9 and TIMP-1 levels (P>0.2). In the patients, there were no significant correlations observed between left ventricular mass, Doppler V(E)/V(A) ratio (an index of diastolic function), blood pressure, left ventricular mass index and either MMP-9 or TIMP-1 levels (all P=NS). Levels of MMP-9 and TIMP-1 were not significantly altered after 2 months of antihypertensive treatment of 29 patients despite mean blood pressure falling from 170/96 to 143/85 mmHg (P<0.001). Correspondingly, there were also no significant alterations in indices of diastolic function and left ventricular mass. Our study suggests that the proteolytic activities of MMP-9 and TIMP-l are depressed in hypertensive patients and were not significantly affected by short-term antihypertensive treatment. The relationship between collagen metabolism in hypertensive subjects, especially in those with cardiac hypertrophy, and the effects of treatment needs to be further explored in larger trials over a longer period of time.     

Increased serum concentrations of tissue inhibitor of metalloproteinase-1 in COPD patients.

Matrix metalloproteinase (MMP)-9 and tissue inhibitors of metalloproteinase (TIMP)-1 concentrations are increased in the sputum of asthma and chronic bronchitis patients, and are thought to be related to airflow obstruction. However, serum concentrations of these enzymes have not been clearly evaluated in patients with chronic obstructive pulmonary disease (COPD). The aim of this study was to examine the serum concentrations of these enzymes in COPD and asthmatic patients in order to determine their relationship with airway obstruction. Serum samples were obtained from 72 patients with COPD: 66 control subjects and 26 patients with asthma. Smoking histories of control subjects were matched with those of COPD patients. Serum concentrations of TIMP-1 and MMP-9 were determined by ELISA. The circulating TIMP-1 concentration was significantly higher in stable COPD patients than in control and asthmatic subjects, and was significantly negatively correlated with forced expiratory volume in one second/forced vital capacity in COPD patients. The molar ratio between MMP-9 and TIMP-1 was significantly lower in COPD patients than in control subjects. In patients with COPD, the serum TIMP-1 concentration was significantly increased during disease exacerbation. In conclusion, the current findings suggest that serum tissue inhibitors of metalloproteinase-1 concentration can be used as a serum marker of airway obstruction and exacerbation in chronic obstructive pulmonary disease patients.     

Dose-dependent effects of inhaled mometasone furoate on airway function and inflammation after allergen inhalation challenge

Comparisons of the potency of different inhaled corticosteroids, delivery devices, and treatment regimens in the management of asthma can only be made when outcome measurements display a dose-dependent effect. These outcomes have been difficult to identify. In this study, we compared in a randomized, double-blind, crossover design, the effects of 6 d treatment with placebo and three doses (50, 100, and 400 microg, twice daily) of mometasone furoate delivered by dry powder inhaler (MF-DPI) on responses after allergen inhalation challenge. Twelve mild asthmatic subjects with dual responses after allergen inhalation were studied. Outcome measurements included early and late asthmatic responses, the change in methacholine airway responsiveness 24 h after challenge, and sputum eosinophilia measured 7 and 24 h after challenge. All three doses of MF-DPI demonstrated similar attenuation of early responses and allergen-induced airway hyperresponsiveness relative to placebo (p < 0.05). The late maximal %fall in FEV(1) after placebo treatment was 23.5% and was significantly reduced in a dose-dependent manner to 12.3%, 11.0%, and 5.9% for the 50-, 100-, and 400-microg twice-daily treatments (p = 0.007). The allergen-induced increase in sputum eosinophilia (x10(4) cells/ml) 24 h after challenge during placebo treatment was 60.2 and was significantly reduced to 24.0, 15.3, and 6.2 for the 50-, 100-, and 400-microg twice-daily treatments. MF-DPI is effective at attenuating allergen-induced early and late responses, airway hyperresponsiveness, and sputum eosinophilia, and dose-response effects exist for the attenuation of the late response.     

Imbalanced matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-1 activities in patients with thromboangiitis obliterans

The pathogenic mechanisms of thromboangiitis obliterans (TAO) are not entirely known and the imbalance of matrix metalloproteinases (MMPs) plays a role in vascular diseases. We evaluated the MMP-2 and MMP-9 circulating levels and their endogenous tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in TAO patients with clinical manifestations. The study included 20 TAO patients (n = 10 female, n = 10 male) aged 38-59 years under clinical follow-up. The patients were classified into two groups: (1) TAO former smokers (n = 11) and (2) TAO active smokers (n = 9); the control group included normal volunteer non-smokers (n = 10) and active smokers without peripheral artery disease (n = 10). Patient plasma samples were used to analyze MMP-2 and MMP-9 levels using zymography, and TIMP-1 and TIMP-2 concentrations were determined by enzyme-linked immunosorbent assays. The analysis of MMP-2/TIMP-2 and MMP-9/TIMP-1 ratios (which were used as indices of net MMP-2 and MMP-9 activity, respectively) showed significantly higher MMP-9/TIMP-1 ratios in TAO patients (p < 0.05). We found no significant differences in MMP-2/TIMP-2 ratios (p > 0.05). We found higher MMP-9 levels and decreased levels of TIMP-1 in the TAO groups (active smokers and former smokers), especially in active smokers compared with the other groups (all p < 0.05). MMP-2 and TIMP-2 were not significantly different in patients with TAO as compared to the control group (p > 0.05). In conclusion, our results showed increased MMP-9 and reduced TIMP-1 activity in TAO patients, especially in active smokers compared with non-TAO patients. These data suggest that smoke compounds could activate MMP-9 production or inhibit TIMP-1 activity.     

基质金属蛋白酶-9和基质金属蛋白酶组织抑制剂-1在高原地区慢性肺心病发病机制中的作用

目的探讨基质金属蛋白酶。9（MMP-9）及其基质金属蛋白酶组织抑制剂-1（TIMP-1）在高原慢性肺心病（HACCP）发病机制中的作用。方法选择高原肺心病急性加重期患者56例（A组）、缓解期患者51例（B组）和健康对照组40例（c组）,采用双抗体夹心酶联免疫吸附法（ELISA）测定诱导痰上清液中MMP-9、TIMP-1表达,并分析其与呼吸功能的关系。结果A组诱导痰中MMP-9、TIMP-1和MMP-9／TIMP-1比值[分别为（976．33±201．65）．g／ml、（624．35±151．22）ng／ml、（1．55±0．16）]显著高于B组[分别为（426．74±123．14）ng／ml、（326．404-112．21）ng／ml、（1．31±0．14）,t值为8．367～17．202,P〈0．01]和C组[分别为（142．55±66．11）ng／ml、（121．78±62．26）ng／ml、（1．14±0．11）,t值为13．642—25．832,P〈0．01];B组显著高于c组（t值为6．827～14．233,P〈0．01）。A、B组诱导痰上清液中MMP-9、TIMP-1、MMP-9／TIMP-1比值与诱导痰中性粒细胞、PaCO：均呈显著正相关（r=0．304～0．743,P〈0．01或P〈0．05）,与FEVl％、Pa02均呈显著负相关（r=-0．314～-0．689,P〈0．01或P〈0．05）。结论MMP-9、TIMP-1和MMP-9／TIMP-1比值失衡在HACCP发病机制中起了一定作用,并与中性粒细胞、PaCO：呈显著正相关,与FEV。％、PaO2呈显著负相关。     

Comparison of levels of matrix metalloproteinase-2 and -3 in patients with ischemic cardiomyopathy versus nonischemic cardiomyopathy

It has been reported that circulating matrix metalloproteinase (MMP) levels are upregulated in patients with chronic heart failure. However, experimental studies indicate that differences in the profiles of MMPs and tissue inhibitors of metalloproteinase (TIMPs) may exist in ischemic compared with nonischemic cardiomyopathy. This study examined whether circulating levels of MMPs and TIMP-1 are related to the pathogenesis of heart failure. Circulating levels of MMP-2, MMP-3, and TIMP-1 were assessed in 52 patients with compensated end-stage chronic heart failure, including 26 patients (mean 64 +/- 7 years; 10 men) with ischemic cardiomyopathy (IC) and 26 (mean age 66 +/- 6 years; 14 men) with idiopathic dilated cardiomyopathy (IDC). Serum MMP-2 (p <0.001) and MMP-3 (p <0.001) levels were higher in patients with IDC than in those with IC. Serum TIMP-1 levels were lower in patients with IDC (p = 0.011) than in those with IC. This study shows that in patients with compensated end-stage chronic heart failure, circulating levels of MMP-2, MMP-3, and TIMP-1 are associated with the pathogenesis of heart failure.     

Increased expression of matrix metalloproteinase-9 associated with gastric ulcer recurrence

AIM: To compare matrix metalloproteinase (MMP)-9 and tissue inhibitor of metalloproteinase (TIMP)-1 in gastric ulcer (GU) and chronic superficial gastritis (CSG). METHODS: This study enrolled 63 patients with GU and 25 patients with CSG. During upper gastroduodenal endoscopy, we took samples of gastric mucosa from the antrum and ulcer site from patients with GU, and samples of antral mucosa from patients with CSG. Mucosal biopsy tissues were cultured for 24 h, and the culture supernatant was measured for levels of MMP-9 and TIMP-1. After receiving eradication therapy for Helicobacter pylori (H. pylori ) and 8 wk proton-pump inhibitor therapy for GU, follow-up endoscopy examination was performed after 6 mo and whenever severe symptoms occurred. RESULTS: Levels of MMP-9 and TIMP-1 at the ulcer site or in the antrum were significantly higher in GU than CSG patients. MMP-9 levels at the ulcer site were significantly higher than in the antrum in GU patients, and had a significantly positive correlation with TIMP-1. MMP-9 levels were significantly higher in H. pylori -positive than H. pylori -negative GU and CSG patients. Levels of MMP-9 or TIMP-1 at the ulcer site were associated with the histological severity of activity and inflammation. About 57 GU patients were followed up, and seven had GU recurrence. H. pyloriinfection and MMP-9 levels were risk factors for the recurrence of GU adjusted for age and sex by multiple logistic regression analysis. CONCLUSION: MMP-9 may perform an important function in gastric ulcer formation and recurrence.     

Impact of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 system on large arterial stiffness in patients with essential hypertension.

The extracellular matrix is vital for maintaining tissue integrity, and the matrix metalloproteinases/tissue inhibitors of metalloproteinases (MMPs/TIMPs) system is involved in the regulation of extracellular matrix metabolism. Extracellular matrix turnover plays an important role in the change of large arterial mechanical properties in hypertension. However, the association of the metalloproteinase-9/tissue inhibitor of metalloproteinase-1 (MMP-9/TIMP-1) system and arterial stiffness is not straightforward and existing data are rather limited. Our objective is to explore the impact of the MMP-9/TIMP-1 system on large arterial stiffness in patients with essential hypertension. An automatic pulse wave velocity (PWV) measuring system was used to examine carotid-femoral PWV (CFPWV) and carotid-radial PWV (CRPWV) as the parameters reflecting central elastic large arterial and peripheral muscular medium-sized arterial elasticity, respectively; and serum MMP-9 and TIMP-1 levels, along with a number of other established biomarkers, were measured by enzyme-linked immunosorbent assay (ELISA) in 202 essential hypertensive patients and 54 age and gender-matched control subjects. Compared with the control subjects, hypertensive patients exhibited higher levels of MMP-9 (p=0.001) and TIMP-1 (p=0.002). Spearman's correlation analysis showed that serum levels of MMP-9 (p=0.014) and TIMP-1 (p=0.005) were significantly and positively correlated with CFPWV in hypertensive patients. A stepwise multiple regressive analysis demonstrated that age, systolic blood pressure, heart rate and TIMP-1 were independent predictors of CFPWV in patients with essential hypertension (adjusted r2=0.458). In conclusion, our results imply that the MMP-9/TIMP-1 system may play an important role in the determination of arterial function, and these findings may have implications for the involvement of MMP-9/TIMP-1 system in the pathophysiology of cardiovascular disease.