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.
Control, rabbit serum-treated (RS; n=27) or anti-neutrophil-antibody-treated (anti-PMN; n=25) C57BL/6 mice underwent aortic elastase perfusion to induce experimental aneurysms. Anti-PMN-treated mice became neutropenic (mean, 349 cells/microL), experiencing an 84% decrease in the circulating absolute neutrophil count (P<0.001) before elastase perfusion. Fourteen days after elastase perfusion, control mice exhibited a mean aortic diameter (AD) increase of 104+/-14% (P<0.0001), and 67% developed AAAs, whereas anti-PMN-treated mice exhibited a mean AD increase of 42+/-33%, with 8% developing AAAs. The control group also had increased tissue neutrophils (20.3 versus 8.6 cells per 5 high-powered fields HPFs; P=0.02) and macrophages (6.1 versus 2.1 cells per 5 HPFs, P=0.005) as compared with anti-PMN-treated mice. There were no differences in monocyte chemotactic protein-1 or macrophage inflammatory protein-1alpha 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 (P=0.017), 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 (n=15) and MMP-8-deficient mice (n=17) were subjected to elastase perfusion, however, ADs at 14 days were no different in size (134+/-7.9% versus 154+/-9.9%; P=0.603), which suggests that MMP-8 serves only as a marker for the presence of neutrophils and is not critical for AAA formation.
Circulating neutrophils are an important initial component of experimental AAA formation. Neutrophil depletion inhibits AAA development through a non-MMP-2/9-mediated mechanism associated with attenuated inflammatory cell recruitment.
Objective Open repair for acute type B dissection with malperfusion is associated with significant morbidity. Thoracic aortic endovascular repair has been proposed as a less-invasive therapy for ...acute type B dissection with malperfusion. Benefits of thoracic aortic endovascular repair include the potential for false lumen thrombosis. Its risks include both early morbidity and mortality, and uncertain late results with potentially unstable landing zones. We present the first long-term analysis of an alternative endovascular approach consisting of percutaneous flap fenestration with true lumen and branch vessel stenting to restore end-organ perfusion. Methods Outcomes were analyzed for 69 patients presenting with acute type B dissection with malperfusion from 1997 to 2008. All patients were evaluated with angiography and treated with a combination of flap fenestration, true lumen, or branch vessel stenting where appropriate. Results Mean age was 57.3 years. Identified malperfused vascular beds included spinal cord (5), mesenteric (40), renal (51), and lower extremity (47). Major morbidity included dialysis need (11), stroke (3), paralysis (2), and 30-day mortality (n = 12, 17.4%). Mean Kaplan–Meier survival was 84.3 months. Although late mortality was associated with age ( P < .0001), neither the type nor the number of malperfused vascular beds correlated with vital status at last follow-up ( P > .4). Freedom from aortic rupture or open repair at 1, 5, and 8 years was 80.2%, 67.7%, and 54.2%, respectively. Conclusion Presentation with acute type B dissection with malperfusion carries a significant risk for both early and late mortality. Percutaneous approaches allow for rapid restoration of end-organ perfusion with acceptable results. These long-term results can serve as comparative data by which to evaluate newer therapies for acute type B dissection with malperfusion, such as thoracic aortic endovascular repair.
: Female gender appears to be protective in the development of abdominal aortic aneurysms (AAAs). This study sought to identify gender differences in cytokine and chemokine expression in an ...experimental rodent AAA model. Male and female rodent aortas were perfused with either saline (control) or elastase to induce AAA formation. Aortic diameter was determined and aortic tissue was harvested on postperfusion days 4 and 7. Cytokine and chemokine gene expression was examined using focused gene arrays. Immunohistochemistry was used to quantify aortic leukocyte infiltration. Data were analyzed by Student's t‐tests and ANOVA.
Elastase‐perfused female rodents developed significantly smaller aneurysms compared to males by day 7 (93 ± 10% vs. 201 ± 25%, P= 0.003). Elastase‐perfused female aortas exhibited a fivefold decrease in expression of the BMP family and ligands of the TNF superfamily compared to males. In addition, the expression of members of the TGF β and VEGF families were three to fourfold lower in female elastase‐perfused aortas compared to males. Multiple members of the interleukin, CC chemokine receptor, and CC ligand families were detectable in only the male elastase‐perfused aortas. Female elastase‐perfused aortas demonstrated a corollary twofold lower neutrophil count (females: 17.5 ± 1.1 PMN/HPF; males: 41 ± 5.2 neutrophils/HPF, P= 0.01) and a 1.5‐fold lower macrophage count (females: 12 ± 1.1 macrophages/HPF; males: 17.5 ± 1.1 macrophages/HPF, P= 0.003) compared to male elastase‐perfused aortas.
This study documents decreased expression of multiple cytokines and chemokines and diminished leukocyte trafficking in female rat aortas compared to male aortas following elastase perfusion. These genes may contribute to the gender disparity seen in AAA formation.
Hyperhomocyst(e)inemia is believed to injure endothelial cells in vivo through a number of mechanisms, including the generation of hydrogen peroxide (H2O2). Earlier in vitro studies demonstrated that ...homocyst(e)ine (Hcy) decreases the biological activity of endothelium-derived relaxing factor and that this decrease can be reversed by preventing the generation of hydrogen peroxide. Here we show that Hcy treatment of bovine aortic endothelial cells leads to a dose-dependent decrease in NO x (p = 0.001 by one-way analysis of variance) independent of endothelial nitric-oxide synthase activity or protein levels and nos3 transcription, suggesting that Hcy affects the bioavailability of NO, not its production. We hypothesized that, in addition to increasing the generation of H2O2, Hcy decreases the cell's ability to detoxify H2O2 by impairing intracellular antioxidant enzymes, specifically the intracellular isoform of glutathione peroxidase (GPx). To test this hypothesis, confluent bovine aortic endothelial cells were treated with a range of concentrations of Hcy, and intracellular GPx activity was determined. Compared with control cells, cells treated with Hcy showed a significant reduction in GPx activity (up to 81% at 250 μm Hcy). In parallel with the decrease in GPx activity, steady-state GPx mRNA levels were also significantly decreased compared with control levels after exposure to Hcy, which appeared not to be a consequence of message destabilization. These data suggest a novel mechanism by which Hcy, in addition to increasing the generation of hydrogen peroxide, may selectively impair the endothelial cell's ability to detoxify H2O2, thus rendering NO more susceptible to oxidative inactivation.
Abstract Objective The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA). Methods Wild-type 8-week-old C56BL/6 male mice (n = 120) were equally ...divided into three groups: (1) BAPN group: 0.2% 3-aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice 2 days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 μL of heat deactivated elastase. (2) Elastase group: mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 μL of the active form of elastase (10.3 mg protein/mL, 5.9 U/mg protein) was applied on top of the infrarenal abdominal aorta adventitia for 5 minutes. (3) BAPN+elastase group: mice were given BAPN drinking water and the active form of elastase application, as above. On postoperative days 7, 14, 21, 28, and 100, aortic samples were collected for histology, cytokine array, and gelatin zymography after aortic diameter measurement. Results Compared with the elastase group, the BAPN+elastase group had a higher AAA formation rate (93% vs 65%; P < .01) with more advanced AAAs (25 of 42 vs 1 of 40 for stage II and III; P < .001). Aneurysms from the BAPN+elastase group demonstrated persistent long-term growth (221.5% ± 36.6%, 285.8% ± 78.6%, and 801% ± 160% on days 21, 28, and 100, respectively; P < .001), with considerable thrombus formation (54%) and rupture (31%) at the advanced stages of AAA development. Cytokine levels (pro-matrix metalloproteinase 9, interleukin-1β, interleukin-6, chemokine C-C motif ligand 5, triggering receptor expressed on myeloid cells 1, monocyte chemotactic protein 1, and tissue inhibitor of metalloproteinase 1) in the BAPN+elastase group were higher than in the elastase group on day 7. After day 7, cytokine levels returned to baseline, with the exception of elevated matrix metalloproteinase 2 activity. By histology, CD3-positive T cells in the BAPN+elastase group were elevated on days 28 and 100. Conclusions A combination of oral BAPN administration and periaortic elastase application induced a chronic, advanced-stage AAA with characteristics of persistent aneurysm growth, thrombus formation, and spontaneous rupture. Future studies should use this model, especially for examining tissue remodeling during the late stages of aneurysm development.
IMPORTANCE: Diversity in academic surgery is lacking, particularly among positions of leadership. OBJECTIVE: To evaluate trends among racial/ethnical minority groups stratified by gender along the ...surgical pipeline, as well as in surgical leadership. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional and longitudinal analysis assessed US surgical faculty census data obtained from the Association of American Medical Colleges faculty roster in the Faculty Administrative Management Online User System database. Surgical faculty members captured in census data from December 31, 2013, to December 31, 2019, were included in the analysis. Faculty were identified from the surgery category of the faculty roster, which includes general surgeons and subspecialists, neurosurgeons, and urologists. MAIN OUTCOMES AND MEASURES: Gender and race/ethnicity were obtained for surgical faculty stratified by rank. Descriptive statistics with annual percentage of change in representation are reported based on faculty rank. RESULTS: A total of 15 653 US surgical faculty, including 3876 women (24.8%), were included in the data set for 2019. Female faculty from racial/ethnic minority groups experienced an increase in representation at instructor and assistant and associate professorship appointments, with a more favorable trajectory than male faculty from racial/ethnic minority groups across nearly all ranks. White faculty maintain most leadership positions as full professors (3105 of 3997 77.7%) and chairs (294 of 380 77.4%). The greatest magnitude of underrepresentation along the surgical pipeline has been among Black (106 of 3997 2.7%) and Hispanic/Latinx (176 of 3997 4.4%) full professors. Among full professors, although Black and Hispanic/Latinx male representation increased modestly (annual change, 0.07% and 0.10%, respectively), Black female representation remained constant (annual change, 0.00004%) and Hispanic/Latinx female representation decreased (annual change, −0.16%). Overall Hispanic/Latinx (20 of 380 5.3%) and Black (13 of 380 3.4%) representation as chairs has not changed, with only 1 Black and 1 Hispanic/Latinx woman ascending to chair from 2013 to 2019. CONCLUSIONS AND RELEVANCE: A disproportionately small number of faculty from minority groups obtain leadership positions in academic surgery. Intersectionality may leave female members of racial/ethnic minority groups more disadvantaged than their male colleagues in achieving leadership positions. These findings highlight the urgency to diversify surgical leadership.
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