Neutrophil Chemotaxis and Neutrophil Elastase in the Aortic Wall in Patients with Abdominal Aortic Aneurysms

Cohen, Jon R.; Keegan, Leo; Sarfati, Isaac; Danna, Debra; Ilardi, Carl F.; Wise, Leslie

doi:10.3109/08941939109141172

Cited by 54 publications

(31 citation statements)

References 9 publications

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“…[2][3][4][5][6][7][8][9] The macrophage, in particular, has been implicated as critical in the pathogenesis. 10 The importance of the neutrophil (polymorphonucleur leukocyte, PMN) during AAA formation has also been established in humans [11][12][13] and, more recently, in a mouse model of aneurysm formation. 14 The mechanisms by which the neutrophil and macrophage are recruited into the aortic wall during aneurysm formation are important.…”

Section: See P 154mentioning

confidence: 99%

L-Selectin–Mediated Neutrophil Recruitment in Experimental Rodent Aneurysm Formation

et al. 2005

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Background-This investigation tested the hypothesis that L-selectin is important in experimental abdominal aortic aneurysm (AAA) formation in rodents. Methods and Results-Rat abdominal aortas were perfused with saline (control) or porcine pancreatic elastase and studied on postperfusion days 1, 2, 4, 7, and 14 (nϭ5 per treatment group per day). Neutrophil (polymorphonucleur leukocyte, PMN) and macrophage counts per high-powered field (HPF) were performed on fixed sections. L-selectin expression and protein levels in aortic tissue were determined by polymerase chain reaction and Western blot, respectively. Elastase-perfused aortic diameters were significantly increased compared with control aortas at all time points except day 1 (PϽ0.05). PMN counts significantly increased in elastase-perfused aortas compared with control aortas at days 1, 2, and 4, reaching maximum levels at day 7 (40.8 versus 0.3 PMNs/HPF, Pϭ0.001). L-selectin mRNA expression in elastase-perfused aortas was 18 (Pϭ0.018), 17 (PϽ0.001), and 8 times (Pϭ0.02) times greater than control aortas at days 1, 2, and 4, respectively. Western blot demonstrated a significant 69% increase in L-selectin protein at day 7 in elastase-as compared with saline-perfused aortas (Pϭ0.005). Subsequent experiments involved similar studies on postperfusion days 4, 7, and 14 of aortas from C57BL/6 wild-type (WT) mice (nϭ21) and L-selectin-knockout (LKO) mice (nϭ19). LKO mice had significantly smaller aortic diameters at day 14 as compared with WT mice (88% versus 123%, Pϭ0.02). PMN counts were significantly greater in elastase-perfused WT mouse aortas as compared with LKO mouse aortas at day 4 after perfusion (12.8 versus 4.8 PMNs/HPF, Pϭ0.02). Macrophage counts were significantly greater at all time points after perfusion in elastase-perfused WT mouse aortas compared with elastase-perfused LKO mouse aortas, with a maximum difference at day 7 after perfusion (13.3 versus 0.5 macrophages/HPF, PϽ0.001). Conclusion-L-selectin-mediated neutrophil recruitment may be a critical early step in AAA formation. (Circulation.2005;112:241-247.)

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Section: See P 154mentioning

confidence: 99%

L-Selectin–Mediated Neutrophil Recruitment in Experimental Rodent Aneurysm Formation

et al. 2005

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“…Tropoelastin and various elastin-derived peptides may also mediate neutrophil, fibroblast, and monocyte/macrophage chemotaxis. [45][46][47] MMP (MMP-1, -2, -3, -9, -12, and -13), 6,41,48 -51 serine proteases (tissue-type plasminogen activator [t-PA]; u-PA; plasmin; and neutrophil elastase), 35,[52][53][54][55] as well as cysteine proteases (cathepsin D, K, L, and S) 56 -59 all localize in aneurysm walls at concentrations higher than occur in normal or stenotic atherosclerotic arteries. Endothelial cells (ECs), SMCs, fibroblasts, or macrophages can all produce these proteinases.…”

Section: Collagenases and Elastases Associate With Aortic Aneurysm Dementioning

confidence: 99%

Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms

Shimizu

Mitchell

Libby

2006

ATVB

564

478

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Abstract-Expansion and rupture of abdominal aortic aneurysms (AAA) result in high morbidity and mortality rates. Like stenotic atherosclerotic lesions, AAA accumulate inflammatory cells, but usually exhibit much more extensive medial damage. Leukocyte recruitment and expression of pro-inflammatory Th1 cytokines typically characterize early atherogenesis of any kind, and modulation of inflammatory mediators mutes atheroma formation in mice. 1 However, the mechanistic differences between stenotic and aneurysmal manifestations of atherosclerosis remain unexplained. We recently showed that aortic allografts deficient in interferon-␥ (IFN-␥) signaling developed AAA correlating with skewed Th2 cytokine environments, suggesting important regulatory roles for Th1/Th2 cytokine balance in modulating matrix remodeling and important implications for the pathophysiology of aortic aneurysm and atherosclerosis. Key Words: aortic aneurysm Ⅲ atherosclerosis Ⅲ cytokine Ⅲ pathogenesis Ⅲ T-lymphocytes Ⅲ transplantation A ortic aneurysms are permanent and localized aortic dilations defined as having diameters 1.5-times greater than normal (ie, Ͼ3 cm diameter for abdominal aortic aneurysms [AAA]). In comparison, the term aortic ectasia describes localized aortic enlargement Ͻ1.5-times normal diameter. 2 Although most aneurysms remain asymptomatic and undiagnosed, risk of rupture increases dramatically when diameters exceed 5.5 cm. Despite surgical advances, the prognosis of ruptured AAA remains poor, and the overall mortality remains high (80% to 90%). 3 Although surgical or endovascular repair constitutes the major therapeutic options for AAA Ͼ5.5 cm, such invasive procedures provide no therapeutic advantage for AAA Ͻ5.5 cm diameter.Most AAA develop below the renal arteries and end above the bifurcation of the iliac arteries; they typically exhibit a fusiform morphology, with symmetrical circumferential enlargement involving all layers of the aortic wall. Less frequently, aneurysms have a saccular form, with aneurysmal degeneration affecting only part of the aortic circumference. The AAA wall usually becomes laminated with thrombus and its intraluminal diameter often appears relatively normal by angiography. Important histological features of aneurysms include chronic adventitial and medial inflammatory cell infiltration, elastin fragmentation and degeneration, and medial attenuation. Collagen (especially types I and III) in the media and adventitia provides tensile strength to the aortic wall. Collagen synthesis increases during the early stages of aneurysm formation, suggesting a repair process. 4 However, in later stages, collagen degradation exceeds its synthesis (accompanied by excessive degradation of other extracellular matrix macromolecules, notably elastin), ultimately favoring AAA rupture. Indeed, AAA exhibit increased local production of enzymes capable of degrading collagen and elastin extracellular matrix proteins. [5][6][7] In AAA, inflammatory cells (polymorphonuclear neutrophils, T cells, B cells, macrophages, mast c...

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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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Neutrophil Chemotaxis and Neutrophil Elastase in the Aortic Wall in Patients with Abdominal Aortic Aneurysms

Cited by 54 publications

References 9 publications

L-Selectin–Mediated Neutrophil Recruitment in Experimental Rodent Aneurysm Formation

L-Selectin–Mediated Neutrophil Recruitment in Experimental Rodent Aneurysm Formation

Inflammation and Cellular Immune Responses in Abdominal Aortic Aneurysms

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

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