Neutrophil-derived matrix metalloproteinase-9 is increased in severe asthma and poorly inhibited by glucocorticoids (original) (raw)
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Neutrophil Depletion Inhibits Experimental Abdominal Aortic Aneurysm Formation
Background-Neutrophils may be an important source of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), two matrix-degrading enzymes thought to be critical in the formation of an abdominal aortic aneurysm (AAA). The purpose of this investigation was to test the hypothesis that neutrophil depletion would limit experimental AAA formation by altering one or both of these enzymes. Methods and Results-Control, rabbit serum-treated (RS; nϭ27) or anti-neutrophil-antibody-treated (anti-PMN; nϭ25) C57BL/6 mice underwent aortic elastase perfusion to induce experimental aneurysms. Anti-PMN-treated mice became neutropenic (mean, 349 cells/L), experiencing an 84% decrease in the circulating absolute neutrophil count (PϽ0.001) before elastase perfusion. Fourteen days after elastase perfusion, control mice exhibited a mean aortic diameter (AD) increase of 104Ϯ14% (PϽ0.0001), and 67% developed AAAs, whereas anti-PMN-treated mice exhibited a mean AD increase of 42Ϯ33%, with 8% developing AAAs. The control group also had increased tissue neutrophils (20.3 versus 8.6 cells per 5 high-powered fields [HPFs]; Pϭ0.02) and macrophages (6.1 versus 2.1 cells per 5 HPFs, Pϭ0.005) as compared with anti-PMN-treated mice. There were no differences in monocyte chemotactic protein-1 or macrophage inflammatory protein-1␣ chemokine levels between groups by enzyme-linked immunosorbent assay. Neutrophil collagenase (MMP-8) expression was detected only in the 14-day control mice, with increased MMP-8 protein levels by Western blotting (Pϭ0.017), and MMP-8 -positive neutrophils were seen almost exclusively in this group. Conversely, there were no statistical differences in MMP-2 or MMP-9 mRNA expression, protein levels, enzyme activity, or immunostaining patterns between groups. When C57BL/6 wild-type (nϭ15) and MMP-8 -deficient mice (nϭ17) were subjected to elastase perfusion, however, ADs at 14 days were no different in size (134Ϯ7.9% versus 154Ϯ9.9%; Pϭ0.603), which suggests that MMP-8 serves only as a marker for the presence of neutrophils and is not critical for AAA formation.
Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms
Journal of Clinical Investigation, 2002
Matrix metalloproteinases (MMPs) 9 and 2 are increased in human abdominal aortic aneurysm (AAA) tissue, but their precise role and potential interaction remain unclear. Experimental induction of aortic aneurysms in mice genetically deficient in these peptidases could provide new insight into AAA pathogenesis. Mice deficient in the expression of MMP-9 (MMP-9KO) or MMP-2 (MMP-2KO) and their corresponding wild-type background mice (WT) underwent AAA induction by abluminal application of calcium chloride (CaCl 2 ). No aneurysm formation was observed at 10 weeks after treatment in either the MMP-9KO or the MMP-2KO mice, whereas the corresponding WT mice showed an average 74% and 52% increase in aortic diameter, respectively. Reinfusion of competent macrophages from the corresponding WT strains into knockout mice resulted in reconstitution of AAA in MMP-9KO but not MMP-2KO mice. These findings suggest that macrophage-derived MMP-9 and mesenchymal cell MMP-2 are both required and work in concert to produce AAA. contributed equally to this work.
Folia biologica, 2017
Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a complex role in the pathogenesis of atherosclerosis. We compared (1) the histopathological findings in patients with abdominal aortic aneurysms (AAA) and aortoiliac occlusive disease (AOD); (2) the expression of MMP-2/MMP-9 and TIMP-1/TIMP-2 in aortic layers, inflammatory cells and smooth muscle cells (SMCs), aiming to identify the common underlying pathogenic mechanisms of the disease development. Samples were obtained from 30 patients with AAA and 30 with AOD. Aortic histology and immunohistochemistry were performed to evaluate inflammatory changes and MMP and TIMP expression. Thrombosis and ulceration were more frequent in AOD than in AAA. The MMP-9 expression was elevated in all aortic layers of AAA patients and in media/adventitia of AOD patients, mainly followed by lower expression of its inhibitor TIMP-1. Higher MMP-9 expression was also found in SMCs and macrophages of both AAA and AOD specimens, whi...
Arteriosclerosis, Thrombosis, and Vascular Biology, 1998
Degradation of the elastic media is a hallmark of abdominal aortic aneurysms (AAAs). We examined the expression of 2 elastolytic matrix metalloproteinases (MMPs), MMP-2 and MMP-9, in AAA aortic tissues compared with those from atherosclerotic occlusive disease (AOD) and nondiseased control tissues. Quantitative competitive reverse transcription-polymerase chain reaction and gelatin zymography showed increased MMP-9 mRNA and protein in both AAA and AOD tissues compared with those in control tissue, but there was no significant difference between AAA and AOD. In contrast, MMP-2 mRNA and protein levels were significantly higher in AAA than in AOD or control tissues. Sequential extraction of the MMPs from the aortic tissue with a physiological salt solution, 2% dimethylsulfoxide (DMSO), and 10 mol/L urea showed that large amounts of MMP-2 and MMP-9 were bound to the matrix. The most conspicuous finding was that the levels of MMP-2 were significantly elevated in the DMSO fraction in AAA tissues compared with AOD and control tissues. In addition, a large portion of MMP-2 found in the DMSO and urea fractions was in the active 62-kDa form, indicating that the precursor of MMP-2 in AAA is largely activated locally and binds to the tissue matrix tightly. By immunolocalization, MMP-9 was found to be primarily produced by macrophages and MMP-2 by mesenchymal cells. The production of MMP-2 was prominent when mesenchymal cells were surrounded by inflammatory cells, suggesting paracrine modulation of MMP-2 expression in AAAs. These observations emphasize that MMP-2 participates in the progression of AAAs by degrading aortic tissue matrix components. (Arterioscler Thromb Vasc Biol. 1998;18:1625-1633.)
Journal of Vascular Surgery, 2014
The results in this paper indicate that active smoking influences vascular cells to increase MMP-2 expression, which contributes to expansion and the rupture risk of AAA. This finding prompts more aggressive control of cardiovascular risk factors in the very early phase of the disease, and particularly AAA screening in smokers. This could even modify monitoring guidelines for AAA in the non-surgical range, and the approach should be more aggressive in patients who continue to smoke. It allows for the possibility that active smokers have a higher risk of rupture than those with the same arterial diameter who do not smoke or who have stopped smoking. Objective: To evaluate the influence of cardiovascular risk factors on levels of matrix metalloproteinases (MMP) 2 and 9 in human abdominal aortic aneurysms (AAA). Methods: Aortic samples were collected from patients who underwent AAA repair (n ¼ 89). Patients were stratified according to the maximum transverse aorta diameter: small diameter (<55 mm), moderate diameter (55e69.9 mm) and large diameter (!70 mm). Aortic walls were studied using real-time PCR and immunohistochemistry. MMP-2, MMP-9, a-actin, CD45, and CD68 transcript levels were determined relative to b-actin. Quantitative data were expressed as median (IQ-range). Results: No differences were found in MMP-2 expression between the patient groups, which was mainly associated with vascular smooth muscle cells (VSMC); however, MMP-9 displayed the maximum level in the moderate-diameter group, associated with infiltrating macrophages. Current smoking (CS) and renal insufficiency (RI) significantly increased local levels of MMP-2 (CS 349.5 [219.5e414.1] vs. no-CS 184.4 [100.0e320.5]; p < .008; RI 286.8 [189.6e410.8] vs. no-RI 177.3 [99.3e326.9]; p ¼ .047). Nevertheless, after stepwise linear regression analysis only CS remained as an independent variable predicting local levels of MMP-2 (p ¼ .002). No risk factors influenced local levels of MMP-9. Conclusions: The results show that local levels of MMP-2, an important factor for AAA development, were increased in current smoking AAA patients. MMP-2 was mainly associated with VSMC. It is suggested that MMP-2 could contribute significantly to the increased AAA growth rate observed in current smoking patients. These findings support inclusion of smokers in screening for aneurysmal disease, and emphasize the need for more aggressive monitoring of aneurysmal disease outside the surgical range in patients who smoke at the time of diagnosis and in those who continue to smoke during follow-up.
Annals of Vascular Surgery, 2013
Background: We searched for any relationship between Chlamydophila pneumoniae, Mycoplasma pneumoniae, matrix metalloproteinase 9 (MMP-9), and tissue inhibitor of metalloproteinase 1 (TIMP-1) in aneurysmatic atherosclerotic lesions, and whether this relationship differed from that in atherosclerotic nonaneurysmatic lesions. Methods: Twenty-eight tissue samples paired by age and sex were grouped as follows: group 1 included 14 nonaneurysmal atherosclerotic fragments obtained from abdominal aortas collected from necropsies; group 2 included 14 aneurysmatic atherosclerotic aortic fragments obtained from patients during corrective surgery. Immunohistochemistry reactions were evaluated for C pneumoniae, M pneumoniae, MMP-9, and TIMP-1 antigens. Both groups were compared using the ManneWhitney test, and the correlations among variables were obtained using the Spearman correlation test. P 0.05 was considered statistically significant. Results: C pneumoniae and M pneumoniae antigens were detected in 100% of cases. A higher amount of C pneumoniae (P ¼ 0.005), M pneumoniae (P ¼ 0.002), and MMP-9 (P ¼ 0.021) was found in adventitia of group 2 with aneurysm. A positive correlation was found in the aneurysm group, as follows: intima C pneumoniae versus adventitia thickness (r ¼ 0.70; P ¼ 0.01), media C pneumoniae versus adventitia C pneumoniae (r ¼ 0.75; P ¼ 0.002), intima C pneumoniae versus media C pneumoniae (r ¼ 0.8; P ¼ 0.00), and adventitia C pneumoniae versus intima M pneumoniae (r ¼ 0.54; P ¼ 0.05); negative correlations were as follows: adventitia thickness and adventitia M pneumoniae (r ¼ À0.65; P ¼ 0.01), media MMP-9 and media thickness (r ¼ À0.55; P ¼ 0.04), TIMP-1 media versus adventitia C pneumoniae (r ¼ À0.86; P ¼ 0.00), and TIMP-1 media versus M pneumoniae intima (r ¼ À0.67; P ¼ 0.03). Nonaneurysmal atherosclerotic group 1 results are as follows: adventitia C pneumoniae versus TIMP-1 media (r ¼ 0.75; P ¼ 0.01) and media C pneumoniae and adventitia C pneumoniae (r ¼ 0.59; P ¼ 0.03). Conclusions: The present work favors a role for coinfection of both M pneumoniae and C pneumoniae in the development of aortic atherosclerotic aneurysm, with increased adventitial inflammation, inhibition of TIMP-1 activity, and increased collagen degradation.
International Journal of Environmental Research and Public Health
Immunosuppressive drugs are widely and chronically used to avoid graft rejection in transplant recipients. However, they are also known to have organotoxic effects and can exert numerous side effects. The aim of this study was to assess whether the chronic treatment of rats with the most commonly used clinical immunosuppressive regimens in organ recipients had an effect on the morphology and function of the aorta. The rats were divided into five groups and each group was chronically treated with different sets of three immunosuppressive drugs (TRG, CRG, MRG, CMG, TMG) for 6 months. The changes were most profound in calcineurin inhibitor-based protocols. TMG protocol treatment was characterized by the most numerous alterations such as morphological changes, changes in the thickness of the tunic media, wider distances between elastic lamellae, an increase in the number of vSMCs and changes in collagen deposition. We concluded that the morphological changes were connected with MMP-2 an...
Journal of Cardiothoracic Surgery, 2009
Background: Matrix metalloproteinases (MMPs) constitute a family of zinc-dependent proteases (endopeptidases) whose catalytic action is the degradation of the extracellular matrix components. In addition, they play the major role in the degradation of collagen and in the process of tissue remodeling. The present clinical study investigated blood serum levels of metalloproteinases-1, -2, -3 and -9 in patients with acute and chronic aortic dissection, thoracic aortic aneurysm and acute myocardial ischemia compared to healthy individuals.
Differential regulation of matrix metalloproteinase activities in abdominal aortic aneurysms
Journal of vascular surgery, 2002
The increased synthesis of matrix metalloproteinases (MMPs) by aortic smooth muscle cells (SMCs) is thought to be involved in the etiopathogenesis of abdominal aortic aneurysms (AAAs), but the functional regulation and the activation states of these MMPs remain unclear. In this study, we assessed the expression levels and the functional regulation of several MMPs in the pathogenesis of AAAs. Human healthy aorta and AAA specimens were homogenized, and the proteolytic activities of MMP-2 and MMP-9 and of the macrophage metalloelastase (MMP-12) were assessed with zymography. Protein expression of MMP-1, MMP-12, membrane-type 1 MMP (MT1-MMP), tissue inhibitor of MMP 1 (TIMP-1), TIMP-2, TIMP-3, alpha-actin, and beta-actin was analyzed with electrophoresis on sodium dodecyl sulfate gels and immunoblotting. MMP-1, MMP-9, and MMP-12 zymogen levels and proteolytic activities were increased in AAAs when compared with healthy aorta. A severe reduction in alpha-actin--positive vascular SMCs was...