An observational study of matrix metalloproteinase (MMP)-9 in cystic fibrosis

Devereux, Graham; Steele, Sandra; Jagelman, Timothy; Fielding, Shona; Muirhead, Robert C. J.; Brady, Jeffrey D.; Grierson, Christal; Brooker, Richard; Winter, John; Fardon, Tom; McCormick, Jonathan; Huang, Jeffrey T.‐J.; Miller, Douglas K.

doi:10.1016/j.jcf.2014.01.010

Cited by 45 publications

(30 citation statements)

References 26 publications

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“…Increases in the MMP-9/TIMP-1 ratio were predominantly due to increases in total MMP-9, with an insufficient increase in TIMP-1 release observed. A recent study reported that plasma TIMP-1 concentration was adversely associated with survival in adults [15]. These counterintuitive findings suggest that the innate regulatory mechanisms of MMP-9 fail to respond correctly in the lung, and, although not assessed in this study, neutrophil elastase mediated degradation of TIMP-1 may contribute to elevated MMP/TIMP-1 in children with elevated neutrophil elastase in BALF [13,18].…”

Section: Discussionmentioning

confidence: 67%

“…Therefore, detection of MMPs is indicative of airway disease, with elevated MMP-9/TIMP-1 ratios linked to worse outcomes in cystic fibrosis across a number of studies [12,13,15,28]. In this assessment of 64 BALF samples taken when children were free of exacerbation, but exhibiting a range of disease severity, the concentrations of MMP-2, MMP-9 and TIMP-1 reported are similar to the minimal data available in children with cystic fibrosis aged <6 years [14,19].…”

Section: Discussionmentioning

confidence: 99%

“…The activity of secreted MMPs is regulated by both an inhibitory protein residue that requires removal for functional activity, as well as inhibition by 1:1 binding of appropriate tissue inhibitors of matrix metalloproteinases (TIMPs) [9]. Of the MMP family, the gelatinases MMP-2 and MMP-9 have previously been reported to correlate with exacerbations, sputum viscosity and worse respiratory outcomes in adolescents and adults with cystic fibrosis [10][11][12][13][14][15]. Studies indicate that neutrophil elastase cleaves the inhibitory protein residue on several MMPs, including MMP-2 and MMP-9 [13,[16][17][18], and might also degrade TIMP-1 [13,18].…”

Section: Introductionmentioning

confidence: 99%

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Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis

et al. 2015

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Neutrophil elastase is the most significant predictor of bronchiectasis in early-life cystic fibrosis; however, the causal link between neutrophil elastase and airway damage is not well understood. Matrix metalloproteinases (MMPs) play a crucial role in extracellular matrix modelling and are activated by neutrophil elastase. The aim of this study was to assess if MMP activation positively correlates with neutrophil elastase activity, disease severity and bronchiectasis in young children with cystic fibrosis.Total MMP-1, MMP-2, MMP-7, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-1 levels were measured in bronchoalveolar lavage fluid collected from young children with cystic fibrosis during annual clinical assessment. Active/pro-enzyme ratio of MMP-9 was determined by gelatin zymography. Annual chest computed tomography imaging was scored for bronchiectasis.A higher MMP-9/TIMP-1 ratio was associated with free neutrophil elastase activity. In contrast, MMP-2/TIMP-2 ratio decreased and MMP-1 and MMP-7 were not detected in the majority of samples. Ratio of active/pro-enzyme MMP-9 was also higher in the presence of free neutrophil elastase activity, but not infection. Across the study cohort, both MMP-9/TIMP-1 and active MMP-9 were associated with progression of bronchiectasis.Both MMP-9/TIMP-1 and active MMP-9 increased with free neutrophil elastase and were associated with bronchiectasis, further demonstrating that free neutrophil elastase activity should be considered an important precursor to cystic fibrosis structural disease. @ERSpublications In young children with CF, activation of MMP-9 by free NE may provide one mechanism driving structural lung disease http://ow.ly/KArB5

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Section: Discussionmentioning

confidence: 67%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis

et al. 2015

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“…A previous study in glioma stem cells also demonstrated that TLR2 up-regulates MMP2 expression (18). MMP9 is predominantly produced by monocytes/ macrophages that abound in sites of chronic inflammation, such as periodontal disease, in which the connective tissue degradation by MMP9 is considered to trigger the disease pathology (24). MMP9 is also essential for initiating the osteoclastic resorption process by removing the collagenous layer from the bone surface before demineralization can start (14).…”

Section: Discussionmentioning

confidence: 99%

MMP2 and MMP9 are Associated with Apical Periodontitis Progression and Might be Modulated by TLR2 and MyD88

et al. 2018

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The aim of this study was to evaluate the expression of MMP2 and MMP9 during apical periodontitis (AP) progression in TLR2 (TLR2 KO) and in MyD88 (MyD88 KO) knockout mice compared to wild type (WT) mice. AP was induced in mandibular first molars of TLR2 KO (n= 18), MyD88 KO (n= 18), and WT mice (n= 18). After 7, 21, and 42 days, the animals were euthanized and the jaws were dissected and subjected to histotechnical processing. Subsequent sections were stained by immunohistochemistry and evaluated for detection of MMP2 and MMP9. Statistical analysis of the semi-quantitative analysis of immunohistochemistry was performed using chi-square test (α = 0.05). In the initial periods of AP progression, an increased expression of MMP9 in the TLR2 KO and MyD88 KO mice was observed. In the final periods of AP progression, a reduction of MMP2 expression and an increase of MMP9 expression in the TLR2 KO mice were observed. MMP2 and MMP9 production was modulated for TLR2 and MyD88 during apical periodontitis progression. MMP2 and MMP9 are Associated w i t h A p i c a l P e r i o d o n t i t i s P r o g r e s s i o n a n d M i g h t b e Modulated by TLR2 and MyD88

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“…54 Plasma MMP-9 levels were elevated in CF patients and indirectly associated with percent predicted FEV 1 and rate of FEV 1 decline. Plasma TIMP-1 levels were inversely associated with mortality.…”

Section: Mmp Levels In Cf Blood Samplesmentioning

confidence: 89%

Matrix metalloproteinases in cystic fibrosis: pathophysiologic and therapeutic perspectives

Owen

Jojas-Quintero²

2016

MNM

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Cystic fibrosis (CF) is the most common inherited disease in the Caucasian population. CF is caused by loss-of-function mutations in the CFTR gene leading to an altered electrolyte and water movement into the airway surface liquid, dehydration of the mucus layer, defective mucociliary clearance, and increased susceptibility to airway bacterial infections. CF is characterized by airway neutrophilic inflammation and activation of airway epithelial cells leading to increased airway levels of various matrix metalloproteinases (MMPs). Herein, we review MMP structure, regulation, and activity, along with the literature on MMPs expression in CF and the contributions of MMPs to CF pathogenesis. Numerous studies report elevated levels of MMPs (especially MMP-8, MMP-7, and MMP-9) in blood and/or lung samples from CF patients and have correlated MMP levels with measures of lung inflammation and injury and/or clinical parameters. No study has yet investigated the contributions of MMPs to the pathogenesis of CF using MMP gene-targeted murine of CF. Based upon the known activities of MMPs in animal models of other lung diseases, we hypothesize that some MMPs (such as MMP-8 and MMP-9) may amplify airway inflammation, and promote airway injury and airway-remodeling processes, or inhibit chloride epithelial transport by inhibiting activation of the CFTR (MMP-2). Other MMPs (such as MMP-7 and MMP-12) may limit the severity of CF by activating host defense proteins to enhance pathogen clearance from the airways, directly killing pathogens that colonize the airways of CF patients and/or promoting epithelial repair. We discuss potential approaches to selectively target MMPs to develop novel therapies that limit the high morbidity and mortality associated with CF.

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An observational study of matrix metalloproteinase (MMP)-9 in cystic fibrosis

Abstract: These associations further justify investigation of MMP-9 and TIMP-1 as biomarkers for short- to medium-term FEV1 decline and mortality in patients with CF.

Cited by 45 publications

References 26 publications

Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis

Matrix metalloproteinase activation by free neutrophil elastase contributes to bronchiectasis progression in early cystic fibrosis

MMP2 and MMP9 are Associated with Apical Periodontitis Progression and Might be Modulated by TLR2 and MyD88

Matrix metalloproteinases in cystic fibrosis: pathophysiologic and therapeutic perspectives

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