Amphiregulin from regulatory T cells promotes liver fibrosis and insulin resistance in non-alcoholic steatohepatitis.

Production of amphiregulin (Areg) by regulatory T (Treg) cells promotes repair after acute tissue injury. Here, we examined the function of Treg cells in non-alcoholic steatohepatitis (NASH), a setting of chronic liver injury. Areg-producing Treg cells were enriched in the livers of mice and humans with NASH. Deletion of Areg in Treg cells, but not in myeloid cells, reduced NASH-induced liver fibrosis. Chronic liver damage induced transcriptional changes associated with Treg cell activation. Mechanistically, Treg cell-derived Areg activated pro-fibrotic transcriptional programs in hepatic stellate cells via epidermal growth factor receptor (EGFR) signaling. Deletion of Areg in Treg cells protected mice from NASH-dependent glucose intolerance, which also was dependent on EGFR signaling on hepatic stellate cells. Areg from Treg cells promoted hepatocyte gluconeogenesis through hepatocyte detection of hepatic stellate cell-derived interleukin-6. Our findings reveal a maladaptive role for Treg cell-mediated tissue repair functions in chronic liver disease and link liver damage to NASH-dependent glucose intolerance.

An Anatomic Classification Scheme for Surgical Planning of Renal Artery Aneurysms.

PURPOSE: Renal artery aneurysm (RAA) is a rare disease. This study proposed and evaluated a new classification for RAA to assist in surgical decision-making. MATERIALS AND METHODS: Single-center data of 105 patients with RAAs from the vascular department of vascular surgery were collected retrospectively. A new classification scheme was proposed. Type I aneurysms arise from the main trunk, accessory branch, or first-order branches away from any bifurcation. Type II aneurysms arise from the first bifurcation with narrow necks (defined as dome-to-neck ratio >2) or from intralobular branches. Type III aneurysms with a wide neck arise from the first bifurcation and affect 2 or more branches that cannot be sacrificed without significant infarction of the kidney. RESULTS: There was 50 (47.62%) type I, 33 (31.43%) type II, and 22 (20.95%) type III aneurysms. The classification assigned endovascular repair as first-line treatment (for type I or II), while open techniques were conducted if anatomically suitable (for type III). A kappa level of 0.752 was achieved by the classification compared with a level of 0.579 from the classic Rundback classification. Technical primary success was achieved in 100% and 96.05%, and symptoms were completely resolved in 100% and 84.85%, while hypertension was relieved in 84.21% and 72.92% of patients receiving open surgery or endovascular repair, respectively. No significant difference was observed for perioperative or long-term complications among the 3 classification types. CONCLUSION: The new classification proved to be a convenient and effective method for facilitating choice of intervention for RAAs. CLINICAL IMPACT: This study proposed and evaluated a new classification scheme for renal artery aneurysms, which proved to be a convenient and effective method for facilitating surgical decision-making. Coil embolization was the first-line treatment if suitable, while aneurysm resection and reconstruction with vein graft were conducted for some complex lesions. The safety and efficacy of both open and endovascular methods were validated.

Long Term Outcomes and Potential Risk Factors for Endovascular Repair of Aortic Pseudoaneurysms in Vascular Behçet's Disease.

OBJECTIVE: This study aimed to analyse long term outcomes and risk factors for endovascular repair of aortic pseudoaneurysms in patients with vascular Behçet's disease (BD). METHODS: Medical records of 26 aortic vascular BD patients who underwent endovascular treatment at the vascular department of Peking Union Medical College Hospital between January 2002 and December 2021 were reviewed retrospectively. Erythrocyte sedimentation rate (ESR) and C reactive protein were used to assess BD activity. Computed tomography angiography (CTA) was obtained pre- and post-operatively for almost all patients. Univariable logistic regression analysis was used to analyse risk factors for endovascular repair, such as inflammatory indicators, drug usage, and stent graft parameters. RESULTS: The abdominal aorta (n = 17) was the most common site of 27 vascular BD pseudoaneurysms in this study. CTA also revealed one aortic arch pseudoaneurysm, seven descending thoracic aortic pseudoaneurysms, one thoraco-abdominal aortic pseudoaneurysm, and one pseudoaneurysm at the aortic bifurcation. Most of the pseudoaneurysms were treated with covered stent grafts. The technical success rate was 96% and no deaths occurred during hospital stay. The mean follow up was 5.8 ± 5.5 years and 31% (8/26) experienced post-operative complications. Overall one, three, and five year event free survival rates were 87%, 78%, and 74%, respectively. Univariable logistic regression analysis revealed that pre-operative ESR ≥ 16.0 mm/h (p = .040), pre-operative glucocorticoid (GC) use ≤ 11.5 days (p = .024), pre-operative immunosuppressant use ≤ 15.5 days (p = .028), and length of proximal landing zone ≤ 1.95 cm (p = .034) were associated with a worse prognoses following endovascular treatment. Proximal oversize ≥ 9.5% (p = .074) was also regarded as a risk factor, although not statistically significant. CONCLUSION: This study further confirmed the feasibility of endovascular repair for aortic vascular BD patients. Risk factors predicting poor prognoses included elevated pre-operative ESR, insufficient pre-operative GC use or immunosuppressant use, inadequate proximal landing zone, and larger proximal oversize percentage.

Blood pressure control and renal function preservation of ex vivo renal artery repair with orthotopic renal autotransplantation for complex renal artery diseases.

OBJECTIVE: To assess the outcome of ex vivo renal artery repair with orthotopic renal autotransplantation for patients with complex renal artery disease. METHODS: The single-center study collected and analyzed the data from patients with complex renal artery disease undergoing ex vivo renal artery repair with orthotopic renal autotransplantation, retrospectively. RESULTS: A total of 21 complex renal artery lesions from 19 patients were included. The mean blood pressure showed a significant decrease from the preoperative to the postoperative period (P < .05). Renal function kept stable for the perioperative period. No significant serum creatinine and estimated glomerular filtration rate alteration was observed compared with the immediate postoperative period (P = .439 and .904, respectively). The median renal cold ischemia time was 35.5 (76) minutes. Two patients developed perioperative complications, one with acute cholecystitis and one with acute renal failure after graft occlusion in a solitary kidney. During the median follow-up of 48 months, one single bypass graft of a solitary kidney was occluded, and four grafts developed restenosis. The primary and primary-assisted patency rates at the 5-year follow-up were 81.3% and 87.5%, respectively. No deaths were observed in the follow-up period. CONCLUSIONS: Ex vivo renal artery reconstruction with orthotopic renal autotransplantation in patients with complex renal artery disease offers stable control of blood pressure and renal function preservation, and should be considered as a potential alternative for other open surgical procedures.

Delphinidin-3-O-glucoside, an active compound of Hibiscus sabdariffa calyces, inhibits oxidative stress and inflammation in rabbits with atherosclerosis.

CONTEXT: Delphinidin-3-O-glucoside (DP) is a bioactive compound of Hibiscus sabdariffa L. (Malvaceae) (Roselle) calyces and exerts endothelial protection and lipid-lowering activities, which provided a basis for the prevention and treatment of cardiovascular diseases. OBJECTIVES: To investigate the therapeutic effects of DP against atherosclerosis. MATERIALS AND METHODS: A rabbit model of atherosclerosis (AS) was established by 12 weeks of a high-fat diet (HFD). The rabbits were divided into five groups: control, AS, simvastatin (4 mg/kg), and two DP groups (10 and 20 mg/kg). After treatment with DP or simvastatin by oral gavage for 12 weeks, the lipid profiles were measured. Histopathological assessment of the aorta was performed by H&E staining. Oxidative stress and inflammation-related markers were analyzed by ELISA kit and real-time RT-PCR. RESULTS: DP (20 mg/kg) decreased serum TG (2.36 ± 0.66 vs. 4.33 ± 0.27 mmol/L for the AS group), TC, LDL-C, and HDL-C (all p < 0.05). DP (20 mg/kg) also reduced lipid levels in the liver and aorta. DP (20 mg/kg) down-regulated the mRNA levels of IL-6, VCAM-1, and NF-κB and up-regulated the mRNA levels of GSH-PX and SOD1. CONCLUSIONS: This study proved that DP alleviated the HFD-induced oxidative stress and inflammation in atherosclerosis rabbits. These results provided the scientific basis for developing novel therapies.

[Effects of Leptin and Leptin-associated Signaling Pathways on the Occurrence and Progression of Abdominal Aortic Aneurysms].

Abdominal aortic aneurysm(AAA) is a chronic dilated artery disease induced by atherosclerosis,infection,trauma and other related causes.The available studies about AAA mainly focus on the inflammatory response,senility,and microenvironmental changes,while the research on the metabolic changes such as glucose metabolism and lipid metabolism remains to be conducted.As a critical regulatory factor in endocrine,glucose,and lipid metabolisms,leptin is associated with a variety of signaling pathways such as adenosine monophosphate-activated protein kinase,Janus kinase/signal transducer and activator of transcription,and cytokine-cytokine receptor,as demonstrated by the KEGG pathway enrichment analysis.Moreover,these signaling pathways are generally involved in regulating the occurrence of AAA.In addition,leptin affects the occurrence of a variety of diseases such as obesity,diabetes,and hyperlipidemia,which contribute to the formation of AAA.Diabetes might be a protective factor for the formation of AAA,while the relationship of hyperlipidemia and obesity with the formation of AAA remains unclear.Therefore,leptin might play an essential role in the formation of AAA.Further studies about the effect of leptin on AAA may provide the potential research direction and facilitate the discovery of therapeutic targets.

Ablation and Inhibition of the Immunoproteasome Catalytic Subunit LMP7 Attenuate Experimental Abdominal Aortic Aneurysm Formation in Mice.

Low-molecular mass protein 7 (LMP7) is a proteolytic subunit of the immunoproteasome that is involved in regulating inflammatory responses. However, the role of LMP7 in the pathogenesis of abdominal aortic aneurysm (AAA) remains unknown. In this study, ApoE knockout (KO) or LMP7/ApoE double KO (dKO) mice were infused with angiotensin II (Ang II, 1000 ng/kg per minute) for up to 28 d. We found that LMP7 expression was significantly upregulated in AAA tissues from ApoE KO mice and human patients. Moreover, Ang II infusion markedly increased the incidence and severity of AAA in ApoE KO mice, which was considerably reduced in LMP7/ApoE dKO mice. Histological alterations, including aortic wall thickening, collagen deposition, elastin fragmentation, and vascular smooth muscle cell apoptosis in AAA tissue of ApoE KO mice, were also significantly attenuated in LMP7/ApoE dKO mice. Interestingly, LMP7/ApoE dKO mice showed a marked reduction of infiltration of CD3+ T cells, especially CD4+ T cells in AAA tissues compared with ApoE KO mice. Moreover, ablation of LMP7 substantially inhibited the differentiation of CD4+ T cells into Th1 and Th17 cells by reducing the activation of multiple transcriptional factors. We also investigated the effects of an LMP7-specific inhibitor PR-957 (also known as ONX 0914) on AAA formation in ApoE KO mice. PR-957 treatment could reduce the AAA incidence and severity. In conclusion, our results provide, to our knowledge, novel evidence that ablation or pharmacological inhibition of LMP7 attenuates Ang II-induced AAA formation, and LMP7 might be a novel therapeutic target for treating AAA in humans.

DEBISim: A simulation pipeline for dual energy CT-based baggage inspection systems1.

BACKGROUND: Materials characterization made possible by dual energy CT (DECT) scanners is expected to considerably improve automatic detection of hazardous objects in checked and carry-on luggage at our airports. Training a computer to identify the hazardous items from DECT scans however implies training on a baggage dataset that can represent all the possible ways a threat item can packed inside a bag. Practically, however, generating such data is made challenging by the logistics (and the permissions) related to the handling of the hazardous materials. OBJECTIVE: The objective of this study is to present a software simulation pipeline that eliminates the need for a human to handle dangerous materials and that allows for virtually unlimited variability in the placement of such materials in a bag alongside benign materials. METHODS: In this paper, we present our DEBISim software pipeline that carries out an end-to-end simulation of a DECT scanner for virtual bags. The key highlights of DEBISim are: (i) A 3D user-interactive graphics editor for constructing a virtual 3D bag with manual placement of different types of objects in it; (ii) An automated virtual bag generation algorithm for creating randomized baggage datasets; (iii) An ability to spawn deformable sheets and liquid-filled containers in a virtual bag to represent plasticized and liquid explosives; and (iv) A GPU-based X-ray forward modelling block for spiral cone-beam scanners used in checked baggage screening. RESULTS: We have tested our simulator using two standard CT phantoms: the American College of Radiology (ACR) phantom and the NIST security screening phantom as well as on a set of reference materials representing commonly encountered items in checked baggage. For these phantoms, we have assessed the quality of the simulator by comparing the simulated data reconstructions with real CT scans of the same phantoms. The comparison shows that the material-specific properties as well as the CT artifacts in the scans generated by DEBISim are close to those produced by an actual scanner. CONCLUSION: DEBISim is an end-to-end simulation framework for rapidly generating X-ray baggage data for dual energy cone-beam scanners.

[Differences of Gut Microbiota Diversity between Patients with Abdominal Aortic Aneurysm and Atherosclerosis].

Objective To investigate the differences of gut microbiota between patients with abdominal aortic aneurysm and atherosclerosis.Methods From December 2018 to June 2019,20 fresh stool samples were collected respectively from the patients with abdominal aortic aneurysm and atherosclerosis treated at the Department of Vascular Surgery,Peking Union Medical College Hospital.The 16S rDNA high-throughput sequencing was employed to compare the composition,abundance,and α and ß diversities of gut microbiota between the two disease groups,and further determine the significantly differential genera.Results The two groups had great similarities in the composition of gut microbiota.There was no statistical difference in α diversity.Although ß diversity did not have statistically significant difference,certain microbial taxa showed differences between the two groups.The LEfSe demonstrated that the abdominal aortic aneurysm group had higher relative abundance of Leuconostocaceae,Ruminococcaceae,Weissella,and Faecalibacterium while lower relative abundance of Firmicuteria,Selenomonadales,and Veillonellaceae.Conclusion The structure of gut microbiota has differences between patients with abdominal aortic aneurysm and atherosclerosis,and sample size should be enlarged to validate the results.

Macrophage pyroptosis is mediated by immunoproteasome subunit ß5i (LMP7) in abdominal aortic aneurysm.

Macrophages contribute to abdominal aortic aneurysm (AAA), but the effect of macrophage on AAA formation is not totally understood. Recent research proved that macrophage pyroptosis plays an important role in many cardiovascular disease. However, whether macrophage pyroptosis is involved in AAA and its mechanism remains unknown. In this study, we found that the pyroptosis significantly increased in AAA tissues. ß5i inhibitor PR-957 treatment or ß5i deficiency markedly ameliorated AAA formation and decreased the pyroptosis. Pyroptosis were also significantly attenuated in bone marrow derived macrophages (BMDM) from ß5i-/- mice compared with the control group when they were subjected to OXLDL. Mechanistically, ß5i may promote activation of NFκB which augment NLRP3 expression. In conclusion, this study suggested macrophages pyroptosis are involved in AAA and inhibition or knockout of ß5i decreased macrophage pyroptosis via IκB/NFκB pathway.

Identification of potential proteases for abdominal aortic aneurysm by weighted gene coexpression network analysis.

Proteases are involved in the degradation of the extracellular matrix (ECM), which contributes to the formation of abdominal aortic aneurysm (AAA). To identify new disease targets in addition to the results of previous microarray studies, we performed next-generation sequencing (NGS) of the whole transcriptome of Angiotensin II-treated ApoE-/- male mice (n = 4) and control mice (n = 4) to obtain differentially expressed genes (DEGs). Identified DEGs of proteases were analyzed using weighted gene coexpression network analysis (WGCNA). RT-qPCR was conducted to validate the differential expression of selected hub genes. We found that 43 DEGs were correlated with the expression of the protease profile, and most were clustered in immune response module. Among 26 hub genes, we found that Mmp16 and Mmp17 were significantly downregulated in AAA mice, while Ctsa, Ctsc, and Ctsw were upregulated. Our functional annotation analysis of genes coexpressed with the five hub genes indicated that Ctsw and Mmp17 were involved in T cell regulation and Cell adhesion molecule pathway, respectively, and that both were involved in general regulation of the cell cycle and gene expression. Overall, our data suggest that these ectopic genes are potentially crucial to AAA formation and may act as biomarkers for the diagnosis of AAA.

Crucial Gene Identification in Carotid Atherosclerosis Based on Peripheral Blood Mononuclear Cell (PBMC) Data by Weighted (Gene) Correlation Network Analysis (WGCNA).

BACKGROUND Many patients are not responsive or tolerant to medical therapies for carotid atherosclerosis. Thus, elucidating the molecular mechanism for the pathogenesis and progression of carotid atherosclerosis and identifying new potential molecular targets for medical therapies that can slow progression of carotid atherosclerosis and prevent ischemic events are quite important. MATERIAL AND METHODS We downloaded the expression profiling data of PBMC in Biobank of Karolinska Endarterectomy (BiKE, GSE21545) for GEO. The WGCNA and DEG screening were conducted. The co-expression pattern between patients with ischemic events (the events group) and patients without ischemic events (the no-events group) were compared. Then, we identified hub genes of each module. Finally, the DEG co-expression network was constructed and MCODE was used to identify crucial genes based on this co-expression network. RESULTS In the study, 183 DEGs were screened and 8 and 6 modules were assessed in the events group and no-events group, respectively. Compared to the no-events group, genes associated with inflammation and immune response were clustered in the green-yellow module of the events group. The hub gene of the green-yellow module of the events group was KIR2DL5A. We obtained 1 DEG co-expression network, which has 16 nodes and 24 edges, and we detected 5 crucial genes: SIRT1, THRAP3, RBM43, PEX1, and KLHDC2. The upregulated genes (THRAP3 and RBM43) showed potential diagnostic and prognostic value for the occurrence of ischemic events. CONCLUSIONS We detected 8 modules for the events group and 6 modules for the no-events group. The hub genes for modules and crucial genes of the DEG co-expression network were also identified. These genes might serve as potential targets for medical therapies and biomarkers for diagnosis and prognosis. Further experimental and biological studies are needed to elucidate the role of these crucial genes in the progression of carotid atherosclerosis.

Distinct features of malignant carotid body tumors and surgical techniques for challengeable lesions: a case series of 11 patients.

PURPOSE: Malignant carotid body tumor (CBT) is a rare disorder with poor prognosis. In this article, we presented the clinical features and surgical management of malignant CBTs at our department, aiming to improve the outcome for treating such lesions. METHODS: A retrospective analysis (2005-2018) of CBT excisions at our institution was performed. About 195 patients with CBTs were identified, among which 11 patients with eleven malignant CBTs were identified and carefully reviewed. Data obtained included demographics, radiological details, intra-operative details, post-operative morbidity, and long-term outcomes. RESULTS: Compared with benign CBTs, malignant CBTs have more advanced Shamblin classification (p < 0.001) and larger tumor size (4.5 ± 2.1 cm vs. 6.7 ± 2.6 cm, p = 0.003). Among the 11 malignant cases, 9 patients underwent surgical resection and 8 cases (8/9, 89%) underwent internal carotid artery (ICA) reconstruction. Intra-operative findings showed that malignant CBTs revealed more severe arterial and nerve adhesions. With the use of specific techniques including pre-reconstruction technique and carotid shunt, all surgeries were successful and no deaths or major complications including stroke or hemiplegia occurred perioperatively and during the follow-up. During the follow-up period (41.6 ± 44.5 months), two patients developed distant metastasis at 7 and 11 years post-operatively. The 5-year and 10-year distant metastasis-free survival rates were 72.7% and 36.4%, respectively. CONCLUSIONS: With more advanced Shamblin classification and larger tumor size, malignant CBTs remain challengeable for surgery due to severe intra-operative hemorrhage, need of vascular reconstruction and cervical nerve injury. Specific surgical techniques including pre-reconstruction technique and carotid shunt are safe and effective to improve the outcome.

Costoclavicular ligament as a novel cause of venous thoracic outlet syndrome: from anatomic study to clinical application.

PURPOSE: Venous thoracic outlet syndrome (VTOS) is a compressive disorder of subclavian vein (SCV); we aimed to investigate the role of costoclavicular ligament (CCL) in the pathogenesis of VTOS. METHODS: A cadaver study was carried out to investigate the presence and morphology of CCL in thoracic outlet regions, as well as its relationship with the SCV. Six formalin-fixed adult cadavers were included, generating 12 dissections of costoclavicular regions (two sides per cadaver). Once CCL was identified, observation and measurement were made of its morphology and dimensions, and its relationship with SCV was studied. To take a step further, a clinical VTOS case was reported to prove the anatomical findings. RESULTS: Two out of twelve costoclavicular regions (2/12, 16.7%) were found to possess CCLs. Both ligaments were located in the left side of two male cadavers and were closely attached to the lateral aspect of sternoclavicular joint capsules. The lateral fibers of the ligament proceed in a superolateral-to-inferomedial manner, while the medial fibers proceed more vertically. Both ligaments were tightly adherent to the SCV, causing significant compression on the vein. In the clinical case, multiple bunches of CCLs were found to compress the SCV tightly intraoperatively. After removing the ligaments, the patient's symptom kept relief during a follow-up period of 2 years. CONCLUSION: Our study demonstrated that CCL could be a novel cause of VTOS by severe compression of SCV. Patients diagnosed with this etiology could get less invasive surgical treatment by simply removing the ligament.

[Research Advances in the Association between Inflammasome and Abdominal Aortic Aneurysm].

The inflammasome is a multiprotein complex localized in the cytoplasm.It can mediate the expressions of various inflammatory cytokines such as interleukin(IL)-1ß and IL-18 and plays a key role in regulating inflammatory response.As sterile inflammation,abdominal aortic aneurysm currently can only be treated by surgery.This article reviews the research advances in the role of inflammasomes in abdominal aortic aneurysm.

Chemokine (C-X-C motif) receptor 2 blockade by SB265610 inhibited angiotensin II-induced abdominal aortic aneurysm in Apo E-/- mice.

Inflammation plays a critical role in the development of abdominal aortic aneurysm (AAA). Chemokine receptor CXCR2 mediates inflammatory cell chemotaxis in several diseases. However, the role of CXCR2 in AAA and the underlying mechanisms remain unknown. In this study, we found that the CXCR2 expressions in AAA tissues from human and angiotensin II (Ang II)-infused apolipoprotein E knockout (Apo E-/-) mice were significantly increased. The pharmacological inhibition of CXCR2 (SB265610) markedly reduced Ang II-induced AAA formation. Furthermore, SB265610 treatment significantly reduced collagen deposition, elastin degradation, the metal matrix metalloprotease expression and accumulation of macrophage cells. In conclusion, these results showed CXCR2 plays a pathogenic role in AAA formation. Inhibition of CXCR2 pathway may represent a novel therapeutic approach to treat AAA.

Surgical Management of Congenital Arteriovenous Fistula near Lateral Cranial Base.

An arteriovenous fistula is an aberrant communication between an artery and a vein. Here is a case in which risk factors including multiple fistulae, dangerous location, and high-flow blood occurred simultaneously. The patient is a 13-year-old boy diagnosed with bilateral arteriovenous fistulae between the jugular vein and carotid artery separately, with cardiac dilatation and pulmonary artery hypertension. We performed right arteriovenous fistulae resection, ligated the involved small vessels, and tightened the internal jugular vein. The tiny left arteriovenous fistulae were treated with transarterial embolism. The blood flow bruit and swelling of his neck completely disappeared, with clear improvement of his life quality, the pulmonary artery pressure has dropped from 54 mmHg to 39 mmHg. Surgery is one of the main therapies of arteriovenous fistula currently, we need to make a balance between good effect and low risk, aiming at early treatment to avoid serious complications.

An association of spleen volume and aortic diameter in patients and in mice with abdominal aortic aneurysm.

BACKGROUND: To investigate the potential mechanism of splenic enlargement in Ang II/APOE model and the associations between the spleen volume and the indices of abdominal aortic aneurysm (AAA) in human. METHODS: To investigate the changes of spleen volume on AAA formation, apolipoprotein E knockout (Apo E-/-) mice were treated with Ang II (1000 ng/kg/min) up to 28 days to generate AAA. We used Magnetic Resonance Imaging (MRI), liquid measurement, H&E and immunohistochemistry to analyze the morphological or pathological changes of spleen. To investigate the changes of spleen volume in human, a retrospective case-control study involving 30 male AAA patients and 25 male controls were performed. Spleen volume was measured on computed tomography images. Univariate analysis and multivariable sequential logistic regression analyses were used to analyze the association between spleen volume and maximal diameter (Dmax). RESULTS: In Ang II/APOE model, we found splenic enlargement in mice with AAA compared with the sham group. Histopathological investigations revealed hypertrophies of splenic follicles and increased populations of CD3+ T cells. In clinic cohort study, univariate analysis revealed higher values in large AAA (Dmax > 5.5 cm,n = 15) compared with the small (Dmax < 5.5 cm,n = 15) for spleen volume (230.6 ± 64.5 cm3 vs. 170.0 ± 32.8 cm3; P = 0.0030). Regression analysis revealed a statistically significant positive linear correlation of spleen volume and Dmax of AAA (r = 0.3611;P = 0.0423). CONCLUSIONS: Mimicking the splenic pathology observed in murine AAA model, there is a strong positive correlation between spleen volume and the Dmax in male AAA patients. As Dmax is a valuable predictor of AAA rupture, the spleen enlargement may be another indicator.

Effect of Bortezomib on Angiotensin â ¡-induced Abdominal Aortic Aneurysm in ApoE-/- Mice.

Objective To investigate the role of proteasome inhibitor bortezomib (BTZ) in inflammatory response in abdominal aortic aneurysm (AAA) formation induced by angiotensin Ⅱ (Ang Ⅱ). Methods Ang Ⅱ-induced ApoE-/- mice AAA models were established. Forty male ApoE-/- mice (8-10-week-old) were randomly and equally divided into four groups:Sham group,BTZ group,Ang Ⅱ group,and Ang Ⅱ+BTZ group.HE staining,immunohistochemical staining,and flow cytometry were used to analyze the inflammatory response. Real-time quantitative polymerase chain reaction (qPCR) was used to analyze the mRNA expression of intercellular cell adhesion molecule-1 (ICAM-1). Western blotting was used to analyze the activation of nuclear factor κB signaling (NF-κB). Results The mean maximum suprarenal aortic diameter (Dmax) of Sham group,BTZ group,Ang Ⅱ group,and Ang Ⅱ+BTZ group were (1.00±0.01),(0.99±0.01),(1.50±0.13),and (1.20±0.04)mm,respectively (F=8.959,P=0.000). The Dmax of Ang Ⅱ group was significantly larger than those of Sham group (P=0.000) and Ang Ⅱ+BTZ group (P=0.015). The incidence of AAA in Ang Ⅱ group,Ang Ⅱ+BTZ group,and Sham group were 60%,17%,and 0,respectively. HE staining revealed that the abdominal aortic wall thickening was more severe in Ang Ⅱ group than in Sham group and Ang Ⅱ+BTZ group,similar with the infiltration of inflammatory cells. Immunohistochemical staining demonstrated that the CD3+T lymphocyte count was significantly higher in Ang Ⅱ group than in Sham group (107.9±15.9 vs. 0,P=0.000) and Ang Ⅱ+BTZ group (107.9±15.9 vs. 0.8±0.5,P=0.000). Flow cytometry also demonstrated that the proportion of the CD3+T lymphocytes of the Ang Ⅱ group [(13.50±0.69)%] was significantly higher than that in the Ang Ⅱ+BTZ group [(10.40±0.78)%] at week 1 (t=3.009,P=0.040),and the proportion of the CD3+T lymphocytes of the Ang Ⅱ group [(22.70±0.93)%] was significantly higher than that in the Ang Ⅱ+BTZ group [(15.10±0.97)%] at week 4 (t=5.654,P=0.005). The qPCR analysis showed that the mRNA expression of ICAM-1 was significantly up-regulated in Ang Ⅱ group than in Sham group (1.93±0.54 vs. 1.00±0.15,P=0.011) and Ang Ⅱ+BTZ group (1.93±0.54 vs. 0.83±0.08,P=0.009). Western blot analysis showed a lower phosphorylation level of inhibitor of NF-κB in the Ang Ⅱ group compared with the Sham group or Ang Ⅱ+BTZ group,accompanied with an increased phosphorylation level of p65. Conclusion Proteasome inhibitor BTZ can attenuate AAA formation partially by regulating T lymphocytes infiltration through regulating the mRNA expression of ICAM-1 regulated by the activation of NF-κB signaling pathway.