Nicotine-Stimulated Elastase Activity Release by Neutrophils in Patients with Abdominal Aortic Aneurysms

Murphy, Edmond A.; Danna-Lopes, D.; Sarfati, Isaac; Rao, Srinivasa K.; Cohen, Jon R.

doi:10.1007/s100169900113

Cited by 40 publications

(24 citation statements)

References 18 publications

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“…Early studies, however, indicated that human AAA tissues express a higher amount of elastase activity compared with normal or atherosclerotic aortas and that elastase activity is highest in patients with ruptured AAAs (13)(14)(15). Immunoreactive neutrophils are also evident within the adventitia and mural thrombus of AAAs, suggesting that release of neutrophil serine proteases might play an important but poorly understood role in aneurysmal degeneration (16,17). This notion is supported by more recent studies indicating that neutrophil depletion can suppress the development of experimental AAAs (18,19).…”

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confidence: 99%

Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms

Pagano

Bartoli

Ennis

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

120

121

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Dipeptidyl peptidase I (DPPI) is a lysosomal cysteine protease critical for the activation of granule-associated serine proteases, including neutrophil elastase, cathepsin G, and proteinase 3. DPPI and granule-associated serine proteases have been shown to play a key role in regulating neutrophil recruitment at sites of inflammation. It has recently been suggested that neutrophils and neutrophil-associated proteases may also be important in the development and progression of abdominal aortic aneurysms (AAAs), a common vascular disease associated with chronic inflammation and destructive remodeling of aortic wall connective tissue. Here we show that mice with a loss-of-function mutation in DPPI are resistant to the development of elastase-induced experimental AAAs. This is in part because of diminished recruitment of neutrophils to the elastase-injured aortic wall and impaired local production of CXC-chemokine ligand (CXCL) 2. Furthermore, adoptive transfer of wild-type neutrophils is sufficient to restore susceptibility to AAAs in DPPI-deficient mice, as well as aortic wall expression of CXCL2. In addition, in vivo blockade of CXCL2 by using neutralizing antibodies directed against its cognate receptor leads to a significant reduction in aortic dilatation. These findings suggest that DPPI and/or granule-associated serine proteases are necessary for neutrophil recruitment into the diseased aorta and that these proteases act to amplify vascular wall inflammation that leads to AAAs. cardiovascular ͉ inflammation ͉ innate immunity ͉ proteases

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mentioning

confidence: 99%

Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms

Pagano

Bartoli

Ennis

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

120

121

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“…Cigarette smoking, which augments NE release in the lung, also contributes to atherothrombosis. 15,16 Inherited deficiency of ␣1-proteinase inhibitor (␣-1-PI), the principle extracellular inhibitor of NE, increases risk of severe earlyonset emphysema. Although less well recognized, humans deficient in ␣-1-PI can also have fibromuscular dysplasia in the carotid and intracranial arteries, indicating an additional role for this enzyme in arterial biology.…”

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confidence: 99%

Neutrophil Elastase in Human Atherosclerotic Plaques

et al. 2003

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Background-Catabolism of the extracellular matrix (ECM) contributes to vascular remodeling in health and disease.Although metalloenzymes and cysteinyl proteinases have garnered much attention in this regard, the role of serine-dependent proteinases in vascular ECM degradation during atherogenesis remains unknown. We recently discovered the presence of the metalloproteinase MMP-8, traditionally associated only with neutrophils, in atheromarelated cells. Human neutrophil elastase (NE) plays a critical role in lung disease, but the paucity of neutrophils in the atheromatous plaque has led to neglect of its potential role in vascular biology. NE can digest elastin, fibrillar and nonfibrillar collagens, and other ECM components in addition to its ability to modify lipoproteins and modulate cytokine and MMP activity. Methods and Results-Fibrous and atheromatous plaques but not normal arteries contained NE. In particular, NE abounded in the macrophage-rich shoulders of atheromatous plaques with histological features of vulnerability. Neutrophil elastase and macrophages colocalized in such vulnerable plaques (nϭ7). In situ hybridization revealed NE mRNA in macrophage-rich areas, indicating local production of this enzyme. Freshly isolated blood monocytes, monocyte-derived macrophages, and vascular endothelial cells in culture produced active NE and contained NE mRNA. Monocytes produced NE constitutively, with little regulation by cytokines IL-1␤, TNF-␣, or IFN-␥ but released it when stimulated by CD40 ligand, a cytokine found in atheroma. Conclusions-These findings point to a novel role for the serine protease, neutrophil elastase, in matrix breakdown by macrophages, a critical process in adaptive remodeling of vessels and in the pathogenesis of arterial diseases.

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“…Increased elastase activity has been implicated in the loss of elastic tissue integrity seen in atherosclerotic aneurysmal disease, and nicotine has been demonstrated to increase elastase release in smokers with aortic aneurysms. 7,8 The reported incidence of coronary vein graft aneurysms is comparable with that reported for infrainguinal vein bypass, [9][10][11] while aneurysmal degeneration of renal artery saphenous vein grafts is less common. 12,13 Coronary vein graft atherosclerosis has been linked to both hypercholesterolemia and hypertriglyceridemia.…”

Section: Discussionmentioning

confidence: 62%

Mega-Aneurysmal Degeneration of a Saphenous Vein Graft Following Infrainguinal Bypass

Corriere¹,

Passman²,

Guzman³

et al. 2004

Vasc Endovascular Surg

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True aneurysm formation in infrainguinal autologous vein grafts is rare. The authors report a case of a patient presenting with extensive aneurysmal degeneration of a femoropopliteal bypass vein graft 13 years after the original operation and 8 years after graft revision and thrombolysis for acute occlusion. Over a 2-year period, the vein graft aneurysm expanded from 2.7 to 4.5 cm maximal diameter. He underwent exclusion and partial resection of the vein graft aneurysm with placement of a new femoropopliteal bypass using reversed saphenous vein from the contralateral leg. Histopathologic examination of the aneurysm revealed intimal fibrosis, medial degeneration, and inflammation. This case and review of the literature suggests that true infrainguinal vein graft aneurysms occur infrequently and massive aneurysm degeneration is even more uncommon. Because of the rarity of true infrainguinal vein graft aneurysms, their etiology remains unclear.

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Nicotine-Stimulated Elastase Activity Release by Neutrophils in Patients with Abdominal Aortic Aneurysms

Cited by 40 publications

References 18 publications

Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms

Critical role of dipeptidyl peptidase I in neutrophil recruitment during the development of experimental abdominal aortic aneurysms

Neutrophil Elastase in Human Atherosclerotic Plaques

Mega-Aneurysmal Degeneration of a Saphenous Vein Graft Following Infrainguinal Bypass

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