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1.
Bronchiectasis is increasingly being recognized as an inflammatory condition of the airways in which pathological permanent dilation occurs. We have obtained endobronchial biopsies in 14 patients with stable bronchiectasis and 15 control subjects. Airway neutrophils, macrophages and tumour necrosis factor-alpha (TNFalpha)-positive cells were stained with monoclonal antibodies and the densities of positive cells in the lamina propria were determined by using a computer image analyser. There was significantly higher neutrophil, macrophage and TNFalpha-positive cell densities in the lamina propria of bronchiectatic than control airways (P < 0.001, P < 0.001 and P=0.0002, respectively). Airway neutrophil density in bronchiectasis but not in controls, correlated with TNFalpha-positive cell density (r=0.71, P=0.004). A significant correlation between airway macrophage and TNFalpha-positive cell densities was demonstrated in both control and bronchiectatic airways (r=0.63, P=0.016 and r=0.60, P=0.02 respectively). Neutrophil density negatively correlated with per cent forced vital capacity (FVC%) predicted among patients with bronchiectasis (r=-0.53, P=0.04). Bronchiectasis patients who were regular sputum producers had a significantly higher macrophage, but not neutrophil density than their counterparts (P=0.02 and P=0.48 respectively). Our original findings suggest that airway macrophages could contribute to neutrophil influx into airway walls through their production of TNFalpha and therefore play an important role in the pathogenesis of bronchiectasis. 相似文献
2.
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. 相似文献
3.
Matrix metalloproteinases and tissue inhibitor of metalloproteinase-1 in sarcoidosis and IPF. 总被引:9,自引:0,他引:9
M T Henry K McMahon A J Mackarel K Prikk T Sorsa P Maisi R Sepper M X Fitzgerald C M O'Connor 《The European respiratory journal》2002,20(5):1220-1227
The purpose of this study was to examine the role of interstitial collagenases, members of the family of matrix metalloproteinases, in the development of pulmonary fibrosis. The activity, levels and molecular forms of collagenases (matrix metalloproteinases (MMP)-1, -8 and -13), gelatinase B (MM P-9) and its main endogenous inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1) were assessed in bronchoalveolar lavage fluid (BALF) from patients with idiopathic pulmonary fibrosis (IPF) and sarcoidosis patients with varying degrees of pulmonary parenchymal involvement. Collagenase activity was elevated in IPF and group 3 sarcoidosis patients. A positive correlation between BALF collagenase activity and MMP-8 levels was also observed. Western immunoblotting revealed the presence of two isoforms of MMP-8 in patient samples; an 80 kD form representing latent enzyme from polymorphonuclear neutrophils and a 55 kD form representing the fibroblast-type proform. MMP-9 levels were also elevated in both IPF and group 3 sarcoidosis patients, while TIMP-1 levels remained normal, indicating a shift in the balance between the enzyme and inhibitor, favouring MMP-9. Matrix metalloproteinase-8 is the major contributor to the bronchoalveolar lavage fluid collagenase activity in the airways of patients with idiopathic pulmonary fibrosis and sarcoidosis and may initiate collagen destruction and remodelling leading to the development of pulmonary fibrosis. 相似文献
4.
BACKGROUND: Investigations using high-resolution CT (HRCT) show that bronchial dilatation (BD) is found in many patients with asthma. However, the pathogenesis and pathophysiologic relevance of BD in asthma are poorly understood. A balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) may control the remodeling of extracellular matrix, and excess MMPs have been associated with destruction or dilatation of airways in patients with bronchiectasis. OBJECTIVES: To study the prevalence of BD as assessed by HRCT according to standard subjective criteria in 37 patients with stable asthma and 10 healthy control subjects, and to examine the relation of BD in asthmatic patients to clinical characteristics and sputum indices, including MMP-9 and TIMP-1 levels. DESIGN: A prospective cohort study. RESULTS: At least one dilated bronchus was present in 23 asthmatic subjects (62%) and 2 control subjects (20%) [p = 0.030]. The ratio of dilated bronchi to all eligible bronchi in each subject (individual BD%) was higher in the asthmatic patients than in the control subjects (11.4 +/- 16.1% vs 1.3 +/- 3.0%, p = 0.011) [mean +/- SD]. Asthmatic patients with (n = 23) and those without BD (n = 14) were similar with regard to age, duration and severity of asthma, atopy, pulmonary function, sputum eosinophil or neutrophil count, and sputum levels of MMP-9 or TIMP-1 and their molar ratio. Individual BD% of asthmatic patients was also unrelated to these clinical and sputum variables. When analysis was confined to the 23 patients with BD, however, individual BD% correlated with the severity score of asthma (r = 0.49, p = 0.023). The results of follow-up HRCT obtained from 19 patients suggested that BD was a fixed rather than transient phenomenon. CONCLUSION: BD is more prevalent in asthmatic patients than in normal subjects and might be associated with the severity of asthma. Cellular inflammation or possible imbalance between MMP-9 and TIMP-1 was not demonstrated in this study to be related to BD in asthma. 相似文献
5.
Increased activity of matrix metalloproteinase-8 and matrix metalloproteinase-9 in induced sputum from patients with COPD 总被引:11,自引:0,他引:11
BACKGROUND: The increased expression of matrix metalloproteinases (MMPs) is considered to be a key factor in the development of COPD. Net MMP activity represents a tightly regulated process, which is not addressed by conventional investigation methods such as messenger RNA or protein expression. Yet, quantitative data on MMP activity in the airways of COPD patients are lacking. METHODS: We used specific immunocapture assays to quantify the activity of MMP collagenase (ie, MMP-1, MMP-8, and MMP-13) and MMP gelatinase (ie, MMP-2 and MMP-9) in the induced sputum of COPD patients (17 patients; FEV(1), 56% predicted) and healthy smokers (17 subjects; FEV(1), 99% predicted). RESULTS: Levels of total and active MMP-8 and MMP-9 were significantly increased in COPD patients vs control subjects, whereas MMP-1 activity levels were similar in both groups. The activity of MMP-2 and MMP-13 remained below the detection threshold of the assays. MMP-8 and MMP-9 activity were strongly related to neutrophilia in both groups, and the results of immunohistochemistry tests on sputum cytospins showed that MMP-9 was expressed in both alveolar macrophages and neutrophils, whereas MMP-8 expression was exclusively observed in neutrophils. A positive correlation was found between sputum MMP-8 and MMP-9 activity and the degree of airflow limitation. CONCLUSION: We demonstrate increased MMP-8 and MMP-9 activity in the airway compartment of patients with mild-to-moderate COPD. This study provides further evidence of an impaired proteinase-antiproteinase balance in COPD patients. 相似文献
6.
The regulation of fibrosis in airway remodeling in asthma 总被引:1,自引:0,他引:1
Fibrosis is one of the key pathological features of airway remodeling in asthma. In the normal airway the amount of collagen and other extracellular matrix components is kept in equilibrium by regulation of synthesis and degradation. In asthma this homeostasis is disrupted due to genetic and environmental factors. In the airways of patients with the disease there is increased extracellular matrix deposition, particularly in the reticular basement membrane region, lamina propria and submucosa. Fibrosis is important as it can occur early in the pathogenesis of asthma, be associated with severity and resistant to therapy. In this review we will discuss current knowledge of relaxin and other key regulators of fibrosis in the airway including TGFβ, Smad2/3 and matrix metalloproteinases. As fibrosis is not directly targeted or effectively treated by current asthma drugs including corticosteroids, characterization of airway fibrosis and how it is regulated will be essential for the development of novel therapies for asthma. 相似文献
7.
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. 相似文献
8.
Soltani A Ewe YP Lim ZS Sohal SS Reid D Weston S Wood-Baker R Walters EH 《The European respiratory journal》2012,39(6):1361-1367
We have investigated whether mast cells are associated with bronchodilator responsiveness and airway vascular changes in chronic obstructive pulmonary disease (COPD) airways. We have previously shown that the reticular basement membrane is hypervascular and the lamina propria is hypovascular in COPD. Bronchial biopsies from 32 COPD subjects, 15 smokers with normal lung function and 17 controls, were immunostained for factor VIII, mast cell tryptase and chymase antibodies. Mast cells in the airway smooth muscle, the reticular basement membrane and the underlying lamina propria were quantitated. 41% of COPD subjects had significant bronchodilator responsiveness, but this was not related to smooth muscle mast cell numbers. The reticular basement membrane had greater mast cell density in all groups compared with controls (p<0.01). In this compartment, perivascular mast cell density was related to hypervascularity. Lamina propria mast cell density was increased only in COPD (p<0.05). Perivascular mast cell density in the lamina propria was not related to its decreased vessel density. Bronchodilator responsiveness in COPD is not related to large airway smooth muscle mast cells of either type; both reticular basement membrane and lamina propria mast cells are increased in COPD patients, and perivascular mast cells may be involved in increased angiogenesis in the reticular basement membrane. 相似文献
9.
Interleukin-8 and airway inflammation] 总被引:3,自引:0,他引:3
H Inoue 《Nihon Kokyūki Gakkai zasshi》1999,37(9):673-679
Airway inflammation is a prominent feature of chronic obstructive diseases of the airways, including asthma, bronchiectasis, chronic bronchitis, and diffuse panbronchiolitis. Neutrophils are implicated in the pathogenesis of these diseases. The present review discusses the role of interleukin-8 (IL-8), a neutrophil chemo-attractant, in neutrophil accumulation in the airways, and the mechanisms of inducing IL-8 expression. IL-8 presents in the sputum of patients with inflammatory airway diseases, and accounts in large part for the chemo-attractant activity present. Focusing on Pseudomonas aeruginosa as the stimulus, it was discovered that when a supernatant of bacterial culture is introduced into the airways in vivo, bacterial products induce IL-8 expression in surface airway epithelial cells and the recruitment of neutrophils into the airways. The neutrophil chemotactic activity of the airway fluid was inhibited by an IL-8 antibody. The luminal IL-8 concentration increased in response to instillation of bacteria, and an inhibitor of neutrophil recruitment markedly reduced the IL-8 levels. From these results, it was speculated that bacteria-induced neutrophil accumulation in the airways involves a cascade of events, and that early neutrophil recruitment in response to bacteria is due to epithelium-derived IL-8, while the amplification of the response is due, at least in part, to IL-8 induction in the neutrophils themselves. 相似文献
10.
Tartrate resistant acid phosphatase (TRAP) positive cells in rheumatoid synovium may induce the destruction of articular cartilage 总被引:8,自引:0,他引:8
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Tsuboi H Matsui Y Hayashida K Yamane S Maeda-Tanimura M Nampei A Hashimoto J Suzuki R Yoshikawa H Ochi T 《Annals of the rheumatic diseases》2003,62(3):196-203
11.
Ho JC Tipoe G Zheng L Leung TM Tsang KW Shum DK Lau CS Mak JC Lam WK Ip MS 《Respiratory medicine》2004,98(4):334-341
Persistent airway inflammation is an important pathogenetic factor in bronchiectasis, and interleukin (IL)-6 is among the mediators implicated in regulation of inflammation in bronchiectatic airways. We postulated that airway secretion with its constituents of cytokines and enzymes would provide an environment for perpetuation of inflammation in vivo. We aimed to determine the action of sputum from patients with bronchiectasis on IL-6 production from cultured normal human bronchial epithelial (NHBE) cells and its modulation by anti-inflammatory drugs in vitro. Cultures of NHBE cells were tested with (i) sputum of bronchiectatic patients, (ii) anti-tumor necrosis factor-alpha (TNF-alpha) pre-treated sputum, or (iii) recombinant human (rh)-TNF-alpha. Alternatively, NHBE cells were incubated with one of the anti-inflammatory drugs before treatment with sputum or rh-TNF-alpha. IL-6 produced into the medium was assayed by ELISA. Sputum in bronchiectasis stimulated IL-6 production from NHBE cells by 1.9 times. This was largely attributable to TNF-alpha as pre-incubation of sputum sol with anti-TNF-alpha almost neutralized the sputum effect. Apart from dexamethasone, the other drugs exerted inhibitory effects on IL-6 production. Ibuprofen suppressed sputum-stimulated IL-6 production to levels above control and effect levelled off at 50-100 microg/mi, contrasting the dose-dependent suppression to control level with MK-663 (0.1-10 microg/ml) and to sub-control levels with triptolide (20-1000 ng/ml). Our results support that sputum in bronchiectasis can stimulate IL-6 production from NHBE cells, and TNF-alpha is an important cytokine mediating the process. The suppressive effects observed with ibuprofen, triptolide and MK-663 warrant further study. 相似文献
12.
Down-regulation of aquaporin 3 in bronchiectatic airways in vivo 总被引:3,自引:0,他引:3
Tsang KW Leung JC Tipoe GL Leung R Yan C Ooi GC Chan HH Lam WK Lai KN 《Respiratory medicine》2003,97(1):59-64
Bronchiectasis is characterized pathologically by permanent abnormal bronchial dilation, and clinically by chronic sputum production. Aquaporin 3 (AQP3), a recently described water channel that is also found in large airway cell membrane, could play a role in the pathogenesis and particularly that of bronchorrhea in bronchiectasis. However, little is known of its in vivo distribution and physiological role in human airways. We have, therefore, performed this quantitative immunohistochemistry study on endobronchial biopsies to evaluate the expression and clinical relevance of AQP3 in patients with idiopathic bronchiectasis (n = 25, 15 F, 64.3 +/- 11.5 years) and control subjects (n = 14, 5 F, 57.5 +/- 12.0 years). Quantitative image analysis was performed to evaluate the expression of AQP3 in the bronchial epithelial cells. Our results show that AQP3 was predominantly expressed in the basal cells of the epithelial layer in both groups. Expression of AQP3 was significantly reduced in the basal, but not columnar, epithelial cells in bronchiectasis compared with control airways (p = 0.02, 0.35). Only bronchiectatic patients with regular sputum production, but not their counterparts, had significant downregulation of epithelial AQP3 expression compared with control airways (p = 0.004, 0.24). Our findings suggest that AQP3 could have an important role in the pathogenesis of increased mucus production in bronchiectasis. 相似文献
13.
Neutrophil granule proteins in bronchoalveolar lavage fluid from subjects with subclinical emphysema. 总被引:18,自引:0,他引:18
T Betsuyaku M Nishimura K Takeyabu M Tanino P Venge S Xu Y Kawakami 《American journal of respiratory and critical care medicine》1999,159(6):1985-1991
Evidence for the contribution of neutrophils to the pathogenesis of pulmonary emphysema is not convincing. We evaluated neutrophil involvement in subclinical pulmonary emphysema by measuring human neutrophil lipocalin (HNL) and two matrix metalloproteinases, gelatinase B (MMP-9) and neutrophil collagenase (MMP-8), in bronchoalveolar lavage fluid (BALF) from 65 community-based older volunteers. HNL is a recently isolated 24-kD protein secreted from secondary granules of activated neutrophils. Despite no appreciable increase in the number of neutrophils, the level of HNL was significantly increased in BALF from subjects with emphysema evidenced by computed tomography regardless of current smoking, as compared with smokers without emphysema. The levels of MMP-9 and MMP-8 were also significantly higher in current smokers with emphysema than in those without emphysema. The appearance of a 130-kD HNL/MMP-9 complex on gelatin zymography and HNL immunoblot indicated neutrophils to be a significant source of MMP-9 in the subjects' BALF. In a 24-h culture medium of alveolar macrophages, only a latent form of MMP-9 was detected, and there was no difference in the level of MMP-9 between the groups. These data provide further evidence for neutrophil involvement in subclinical pulmonary emphysema. 相似文献
14.
基质金属蛋白酶在大鼠慢性阻塞性肺疾病模型气道细胞外基质重塑中的作用 总被引:11,自引:0,他引:11
目的 研究基质金属蛋白酶(MMPs)及其组织抑制剂(TIMP-1)在大鼠慢性阻塞性肺疾病(COPD)模型气道和肺组织中的表达及其在细胞外基质重塑中的作用。方法 采用熏香烟加气管注内毒素法,建立大鼠COPD模型,观察其气道重塑的病理改变、肺功能及血气变化;用生化法测定支气管肺组织羟脯氨酸含量;用免疫组化法观察MMP-9、MMP-2及TIMP-1的蛋白定位及表达;用逆转录-聚合酶链反应法测定MMP-9、MMP-2及TIMP-1mRNA表达;用SDS-PAGE明胶酶谱学测定支气管肺组织MMPs酶活性。结果 用熏香烟加气管注内毒素法建立的大鼠COPD模型,其病理形态学改变、肺功能及血气变化均与人类COPD的改变相似。COPD模型组支气管肺组织羟脯胺酸含理、支气管黏膜下成纤维细胞、淋巴细胞数和肺泡巨噬细胞数及以I型胶原为主的细胞外基质含量显著高于健康对照组(P值均<0.001)。COPD模型组MMP-9、MMP-2及TIMP-1在气道上皮、成纤维细胞、肺泡巨噬细胞、血管内皮细胞及部分肺泡壁细胞表达均明显增强,支气管肺组织MMP-9、MMP-2及TIMP-1 mRNA表达亦显著增强,72000MMP-2及92000 MMP-9酶活性亦显著增高。结论 MMPs表达增强提示细胞外基质降解增加,支气管肺结构破坏增加。TIMP-1在抑制MMPs活性的同时,促进成纤维细胞增生及胶原等合成增多,是导致细胞外基质修复和重塑的重要机制之一。 相似文献
15.
16.
目的探讨克拉霉素对于难治性哮喘患者,特别是对非嗜酸粒细胞型哮喘(NEA)亚组患者的疗效。方法难治性哮喘患者(n=45)被随机分配至克拉霉素组(500 mg bid)和安慰剂组,共8周。结果克拉霉素与安慰剂相比,明显降低了气道IL-8的浓度和中性粒细胞的数目,改善了生活质量评分。另外NE和MMP-9的浓度得到降低,这对于NEA患者最为显著。结论克拉霉素可调节难治性哮喘患者气道内IL-8水平和中性粒细胞的聚集和活性,降低非嗜酸粒细胞性炎症反应,特别是中性粒细胞性炎症反应。 相似文献
17.
Henry MT McMahon K Costello C Fitzgerald MX O'Connor CM 《Experimental lung research》2002,28(2):85-97
The naturally occurring neutrophil elastase inhibitors, alpha1-proteinase inhibitor (alpha1PI), secretory leukocyte proteinase inhibitor (SLPI), and elafin, are potential therapeutic agents in the treatment of neutrophil-mediated lung disease. However alpha1PI has been shown to be susceptible to inactivation by matrix metalloproteinases (MMPs) released by neutrophils, particularly neutrophil collagenase (MMP-8). The aim of this study was to determine if SLPI and elafin are similarly susceptible to degradation by this neutrophil-specific MMP. The effect of MMP-8 on SLPI and elafin was assessed by determining the neutrophil elastase inhibitory capacity (NEIC) and electrophoretic protein profile of both inhibitors following exposure to purified MMP-8. As a positive control, the effect of MMP-8 alpha1PI was assessed in parallel. Although treatment of alpha1PI with MMP-8 resulted in a significant decrease in its NEIC (P = .025), no similar decrease was observed with SLPI or elatin. Electrophoretic analysis confirmed digestion of alpha1PI by MMP-8 but no digestion of either SLPI or elafin was observed. These results demonstrate that SLPI and elafin are resistant to proteolytic inactivation by MMP-8, a property that may enhance their therapeutic application in neutrophil-mediated inflammatory lung disease. 相似文献
18.
Effect of a long-acting beta2-agonist over three months on airway wall vascular remodeling in asthma. 总被引:7,自引:0,他引:7
B E Orsida C Ward X Li R Bish J W Wilson F Thien E H Walters 《American journal of respiratory and critical care medicine》2001,164(1):117-121
There are few data regarding the potential effects of antiasthma treatment on indices of airway remodeling, such as the increased subepithelial airway vascularity in patients with asthma. We studied 45 symptomatic subjects with asthma who were receiving treatment with low dose inhaled corticosteroids (ICS) (range 200-500 microg twice a day) and 28 normal subjects without asthma as a control population. Subjects underwent bronchoscopy with airway biopsy and subjects with asthma were then randomized to receive supplementary inhaled salmeterol 50 microg twice a day, fluticasone propionate 100 microg twice a day, or placebo for 3 mo in addition to their baseline ICS. Biopsy of the airway was then repeated. The biopsies were analyzed for vascular structures in the subepithelial lamina propria. Sufficient biopsy material was available for analysis of vascularity in 34 of the subjects with asthma and 28 of the normal subjects. We confirmed that airways of subjects with asthma had a significant increase in the number of vessels/mm2 of lamina propria compared with airways of normal subjects (524 +/- 137 vessels/mm2, n = 34 versus 425 +/- 130 vessels/mm2, n = 28; p = 0.004). There was a decrease in the density of vessels of lamina propria after treatment only in the salmeterol group compared with baseline (before, 535 +/- 153 vessels/mm2 versus after, 400 +/- 142 vessels/mm2; n = 12; p = 0.04). There was no significant change within the fluticasone (n = 11) or placebo (n = 11) treatment groups, but also no significant differences between the groups. Notably, no treatment was associated with increased airway wall vascularity. The demonstrated fall in vessel number within the salmeterol-treated group may suggest an advantageous effect of long-acting beta2-agonists on this manifestation of airway remodeling over the 3-mo time scale of this study, which is complementary to the action of ICS on airway vascularity. 相似文献
19.
Hartog CM Wermelt JA Sommerfeld CO Eichler W Dalhoff K Braun J 《American journal of respiratory and critical care medicine》2003,167(4):593-598
In hospital-acquired pneumonia, extracellular matrix destruction is common and may be caused by excessive activity of matrix metalloproteinases (MMPs). Thirty patients with hospital-acquired pneumonia and 16 control subjects were studied. We evaluated the concentrations of MMP-8, MMP-9, and tissue inhibitor of metalloproteinase-1 in mini-bronchoalveolar lavage fluid (mini-BALF) and blood using zymography and specific immunoassays. In patients with hospital-acquired pneumonia concentrations of MMP-8 and MMP-9 in mini-BALF were increased 10-fold, whereas their specific inhibitor tissue inhibitor of metalloproteinase-1 was not concomitantly increased. In 80% of patients with pneumonia, but in none of the control subjects, the active form of MMP-9 was detected by zymography. Zymography furthermore showed the banding pattern of neutrophil-derived MMP-9, indicating that neutrophils were the main source of MMP-9. Comparison of neutrophils from blood and mini-BALF showed higher basal release of MMPs by pulmonary neutrophils. Stimulation analysis indicated that pulmonary neutrophils were already maximally activated. In patients with detection of potentially pathogenic microorganisms, concentrations of MMPs were fivefold increased compared with patients with negative cultures. Furthermore, MMP-levels were related to clinical severity. These are the first data suggesting that neutrophil-derived MMPs are increased in hospital-acquired pneumonia in association to the detection of causative microorganisms and clinical severity. 相似文献
20.
P G Gibson P A B Wark J L Simpson C Meldrum S Meldrum N Saltos M Boyle 《The European respiratory journal》2003,21(4):582-588
Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the fungus Aspergillus fumigatus, causing severe asthma that may progress to bronchiectasis. Sputum neutrophilia can occur in association with sputum eosinophilia and correlates with the degree of bronchiectasis. The mechanisms of sputum neutrophilia in ABPA are not known. The aim of this study was to investigate the role of the chemokine interleukin (IL)-8 in sputum neutrophilia in ABPA. Induced sputum was obtained from subjects with ABPA (n=29), and compared to nonsensitised asthma (n=9) and healthy controls (n=21). Semiquantitative polymerase chain reaction was used to assess IL-8 gene expression in induced sputum and IL-8 protein was measured by enzyme-linked immunosorbent assay. Sputum IL-8 protein was significantly higher in ABPA compared to asthma and controls. IL-8 messenger ribonucleic acid/glyceraldehyde-3-phosphate dehydrogenase ratio was elevated in ABPA compared to asthma and controls. Sputum IL-8 correlated with sputum neutrophils, matrix metalloproteinase-9 levels and forced expiratory volume in one second. Interleukin-8 gene expression and protein release were increased in allergic bronchopulmonary aspergillosis and correlated with airway neutrophilia and airway obstruction. The interleukin-8-mediated neutrophil influx in allergic bronchopulmonary aspergillosis may induce lung damage via release of matrix metalloproteinase-9, potentially leading to bronchiectasis. 相似文献