interleukin-8 and Aortic-Aneurysm--Abdominal

Doxycycline has been shown to effectively inhibit aneurysm formation in animal models of abdominal aortic aneurysm. Although this effect is ascribed to matrix metalloproteinase-9 inhibition, such an effect is unclear in human studies. We reevaluated the effect of doxycycline on aortic wall protease content in a clinical trial and found that doxycycline selectively reduces neutrophil-derived proteases. We thus hypothesized that doxycycline acts through an effect on vascular inflammation.. Sixty patients scheduled for elective open aneurysmal repair were randomly assigned to 2 weeks of low-, medium-, or high-dose doxycycline (50, 100, or 300 mg/d, respectively) or no medication (control group). Aortic wall samples were collected at the time of operation, and the effect of doxycycline treatment on vascular inflammation was evaluated. Independently of its dose, doxycycline treatment resulted in a profound but selective suppression of aortic wall inflammation as reflected by a selective 72% reduction of the aortic wall neutrophils and a 95% reduction of the aortic wall cytotoxic T-cell content (median values; P<0.00003). Evaluation of major inflammatory pathways suggested that doxycycline treatment specifically quenched AP-1 and C/EBP proinflammatory transcription pathways (P<0.0158, NS) and reduced vascular interleukin-6 (P<0.00115), interleukin-8 (P<0.00246, NS), interleukin-13 (P<0.0184, NS), and granulocyte colony-stimulating factor (P<0.031, NS) protein levels. Doxycycline was well tolerated; there were no adverse effects.. A brief period of doxycycline treatment has a profound but selective effect on vascular inflammation and reduces aortic wall neutrophil and cytotoxic T-cell content. Results of this study are relevant for pharmaceutical stabilization of the abdominal aneurysm and possibly for other inflammatory conditions that involve neutrophils and/or cytotoxic T cells.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Aorta; Aortic Aneurysm, Abdominal; CCAAT-Enhancer-Binding Proteins; Doxycycline; Enzyme Inhibitors; Female; Humans; Interleukin-6; Interleukin-8; Male; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Middle Aged; Neutrophils; T-Lymphocytes, Cytotoxic; Transcription Factor AP-1; Transcription Factor RelA; Vasculitis

Perivascular adipose tissue (PVAT) contributes to vascular homeostasis and is increasingly linked to vascular pathology. PVAT density and volume were associated with abdominal aortic aneurysm (AAA) presence and dimensions on imaging. However, mechanisms underlying the role of PVAT in AAA have not been clarified. This study aimed to explore differences in PVAT from AAA using gene expression and functional tests.. Human aortic PVAT and control subcutaneous adipose tissue were collected during open AAA surgery. Gene analyses and functional tests were performed. The control group consisted of healthy aorta from non-living renal transplant donors. Gene expression tests were performed to study genes potentially involved in various inflammatory processes and AAA related genes. Live PVAT and subcutaneous adipose tissue (SAT) from AAA were used for ex vivo co-culture with smooth muscle cells (SMCs) retrieved from non-pathological aortas.. Adipose tissue was harvested from 27 AAA patients (n [gene expression] = 22, n [functional tests] = 5) and five control patients. An increased inflammatory gene expression of PTPRC (p = .008), CXCL8 (p = .033), LCK (p = .003), CCL5 (p = .004) and an increase in extracellular matrix breakdown marker MMP9 (p = .016) were found in AAA compared with controls. Also, there was a decreased anti-inflammatory gene expression of PPARG in AAA compared with controls (p = .040). SMC co-cultures from non-pathological aortas with PVAT from AAA showed increased MMP9 (p = .033) and SMTN (p = .008) expression and SAT increased SMTN expression in these SMC.. The data revealed that PVAT from AAA shows an increased pro-inflammatory and matrix metallopeptidase gene expression and decreased anti-inflammatory gene expression. Furthermore, increased expression of genes involved in aneurysm formation was found in healthy SMC co-culture with PVAT of AAA patients. Therefore, PVAT from AAA might contribute to inflammation of the adjacent aortic wall and thereby plays a possible role in AAA pathophysiology. These proposed pathways of inflammatory induction could reveal new therapeutic targets in AAA treatment.

Topics: Adipose Tissue; Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Case-Control Studies; Chemokine CCL5; Cytoskeletal Proteins; Female; Humans; Interleukin-8; Leukocyte Common Antigens; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Male; Matrix Metalloproteinase 9; Middle Aged; Muscle Proteins; Myocytes, Smooth Muscle; PPAR gamma; RNA, Messenger

There are indications for elevated CXCL8 levels in abdominal aortic aneurysm disease (AAA). CXCL8 is concurrently involved in neutrophil-mediated inflammation and angiogenesis, two prominent and distinctive characteristics of AAA. As such we considered an evaluation of a role for CXCL8 in AAA progression relevant. ELISA's, real time PCR and array analysis were used to explore CXCL8 signaling in AAA wall samples. A role for CXCL8 in AAA disease was tested through the oral CXCR1/2 antagonist DF2156A in the elastase model of AAA disease. There is an extreme disparity in aortic wall CXCL8 content between AAA and aortic atherosclerotic disease (median [IQR] aortic wall CXCL8 content: 425 [141-1261] (AAA) vs. 23 [2.8-89] (atherosclerotic aorta) µg/g protein (P < 1 · 10

Topics: Aged; Animals; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Atherosclerosis; Disease Models, Animal; Disease Progression; Gene Expression Profiling; Humans; Inflammation Mediators; Interleukin-8; Male; Mice, Inbred C57BL; Pancreatic Elastase; Receptors, Interleukin-8A; Receptors, Interleukin-8B; Signal Transduction; Sulfonamides; Tissue Array Analysis

AAA (abdominal aortic aneurysm) is an important cause of sudden death in older adults, but there is no current effective drug therapy for this disease. The UCNs (urocortins1-3) and their receptors: CRFR (corticotrophin-releasing factor receptor)-1 and -2 have been implicated in various CVDs (cardiovascular diseases). We assessed the relative expression of UCN1-3 in AAA by qRT-PCR (quantitative reverse transcription-PCR) and ELISA, and examined in vitro how UCN2 affects human aortic VSMC (vascular smooth muscle cell) Akt phosphorylation, pro-inflammatory cytokine IL (interleukin)-6 secretion, proliferation, cell cycle and apoptosis. UCN2 and CRFR2 expression were significantly up-regulated in biopsies from the AAA body. AAA body biopsies released high amounts of UCN2 in vitro. Median plasma UCN2 concentrations were 2.20 ng/ml (interquartile range 1.14-4.55 ng/ml, n=67) in AAA patients and 1.11 ng/ml (interquartile range 0.76-2.55 ng/ml, n=67) in patients with non-aneurysmal PAD (peripheral artery disease) (P=0.001). Patients with UCN2 in the highest quartile had a 4.12-fold (95% confidence interval, 1.37-12.40) greater prevalence of AAA independent of other risk factors, P=0.012. In vitro, UCN2 significantly inhibited VSMC Akt phosphorylation and proliferation in a dose-dependent manner. UCN2 induced VSMC G1 cell-cycle arrest and increased IL-6 secretion over 24 h. The CRFR2 antagonist astressin-2B significantly abrogated the effects of UCN2 on VSMCs. In conclusion, UCN2 is significantly associated with AAA and inhibits VSMC proliferation by inducing a G1 cell cycle arrest suggesting a plausible regulatory role in AAA pathogenesis.

Topics: Aortic Aneurysm, Abdominal; Cell Proliferation; Cells, Cultured; Corticotropin-Releasing Hormone; Humans; Interleukin-8; Muscle, Smooth, Vascular; Phosphorylation; Proto-Oncogene Proteins c-akt; Receptors, Corticotropin-Releasing Hormone; Urocortins

Independent of their blood pressure lowering effect, ACE inhibitors are thought to reduce vascular inflammation. The clinical relevance of this effect is unclear with the current knowledge. Abdominal aortic aneurysms (AAA) are characterized by a broad, non-specific inflammatory response, and thus provide a clinical platform to evaluate the anti-inflammatory potential of ACE inhibitors.. Eleven patients scheduled for open AAA repair received ramipril (5 mg/day) during 2-4 weeks preceding surgery. Aortic wall samples were collected during surgery, and compared to matched samples obtained from a biobank. An anti-inflammatory potential was evaluated in a comprehensive analysis that included immunohistochemistry, mRNA and protein analysis. A putative effect of ACE inhibitors on AAA growth was tested separately by comparing 18-month growth rate of patients on ACE inhibitors (n = 82) and those not taking ACE inhibitors (n = 204). Ramipril reduces mRNA expression of multiple pro-inflammatory cytokines such as IL-1β, IL-6, IL-8, TNF -α, Interferon-[Formula: see text], and MCP-1, as well as aortic wall IL-8 and MCP-1 (P = 0.017 and 0.008, respectively) protein content. The is followed by clear effects on cell activation that included a shift towards anti-inflammatory macrophage (M2) subtype. Evaluation of data from the PHAST cohort did not indicate an effect of ACE inhibitors on 18-month aneurysm progression (mean difference at 18 months: -0.24 mm (95% CI: -0.90-0.45, P = NS).. ACE inhibition quenches multiple aspects of vascular inflammation in AAA. However, this does not translate into reduced aneurysm growth.. Nederlands Trial Register 1345.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Aorta; Aortic Aneurysm, Abdominal; Blood Vessels; Female; Gene Expression Regulation; Humans; Inflammation; Interleukin-6; Interleukin-8; Macrophages; Male; Middle Aged; Ramipril; RNA, Messenger

To evaluate the impact of endograft type on the inflammatory response after elective endovascular repair of abdominal aortic aneurysms.. From January 2011 to November 2011, we included 100 consecutive patients who underwent elective abdominal aortic aneurysm endovascular repair. Thirteen patients were excluded from the analysis: four with cancer, three with autoimmune disease, two because of recent infection, two who were receiving long-term anti-inflammatory medication, and two because of recent surgery. Temperature, white blood cell count, platelet count, and serum concentrations of cytokines (interleukin [IL]-6, IL-8, and IL-10) were measured preoperatively, 24 hours postoperatively, and 48 hours postoperatively. The study sample was divided into four groups with respect to the type of endograft used: group A, n = 28 (Anaconda; Sulzer Vascutek, Bad Soden, Germany); group B, n = 26 (Zenith; Cook Inc, Bloomington, Ind); group C, n = 23 (Excluder; W. L. Gore and Assoc, Flagstaff, Ariz); and group D, n = 10 (Endurant; Medtronic, Minneapolis, Minn). Endograft configurations included bifurcated grafts only.. Epidemiologic characteristics, atherosclerotic risk factors, type of anesthesia, mean blood loss during surgery, and baseline serum levels of cytokines did not differ among the four groups. Mean elevated temperature was more pronounced postoperatively in group A. Serum levels of IL-6 and IL-10 were significantly higher 24 hours and 48 hours postoperatively compared with preoperative levels in all groups. Patients in group C showed the smallest increase in levels of serum IL-6 and IL-10 at 24 hours and 48 hours postoperatively. Mean difference in cytokine levels after aneurysm exclusion was greater for group A vs group C (P < .01) compared with group A vs B (P < .05). No differences in the mortality and morbidity rates were observed among the four groups.. Endograft type appears to influence the inflammatory response after endovascular aortic repair. The postimplantation syndrome was apparent during the first 24 hours and decreased afterward. Anaconda and Zenith endografts induced a more intense inflammatory response. A "milder" inflammatory activation was observed in patients with an Excluder endograft. The postimplantation syndrome was not associated with perioperative adverse clinical events showing a benign course. The possible long-term sequelae of postimplantation syndrome require further investigation.

Topics: Aged; Analysis of Variance; Aortic Aneurysm, Abdominal; Biomarkers; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Body Temperature Regulation; Chi-Square Distribution; Elective Surgical Procedures; Endovascular Procedures; Female; Humans; Inflammation; Inflammation Mediators; Interleukin-10; Interleukin-6; Interleukin-8; Leukocyte Count; Male; Platelet Count; Prospective Studies; Prosthesis Design; Risk Factors; Stents; Time Factors; Treatment Outcome; Up-Regulation

Levels of proinflammatory mediators in unwashed salvaged blood from abdominal aortic aneurism (AAA) surgery are unknown. We hypothesized that there are higher levels of these mediators in unwashed blood salvaged in AAA surgery compared to hip replacement surgery.. Ten patients scheduled for AAA surgery (Group A) and 10 patients for total hip replacement surgery (Group H) were included. Blood samples from the autotransfusion set were obtained during surgery and arterial samples before, during, and 6 hours after surgery. Determination of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, activated complement 3 (C3a), and high-sensitivity C-reactive protein (CRP) were performed. Salvaged blood was not retransfused.. Levels (median [range]) of IL-8 in blood in the salvage system were higher in Group A versus Group H (215.3 [22.5-697.2] vs. 35.3 [16.7-66.6] pg/mL; p = 0.002). Higher levels of IL-6 were also seen in Group A versus Group H (60.0 [52.6-62.2] vs. 42.34 [19.4-62.2] pg/mL; p = 0.049). Levels of IL-6 in blood sampled during surgery were approximately fivefold higher in Group A versus Group H (p = 0.023), whereas approximately 70% higher levels of C3a were observed in Group H versus Group A (p = 0.021). Postoperative concentrations of IL-1β (p = 0.002), IL-6 (p = 0.001), and IL-8 (0.005) were higher in Group A versus Group H.. Salvaged blood in AAA surgery contains substantially higher levels of proinflammatory mediators compared to blood in total hip replacement surgery.

Topics: Aged; Aortic Aneurysm, Abdominal; Arthroplasty, Replacement, Hip; Blood Transfusion, Autologous; C-Reactive Protein; Complement Activation; Complement C3a; Female; Humans; Inflammation Mediators; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Middle Aged; Operative Blood Salvage; Postoperative Complications; Tumor Necrosis Factor-alpha

Abdominal aortic aneurysms (AAAs) are characterised by chronic transmural inflammation. This study investigated the expression of interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) within the AAA, and their relationship with mural inflammation.. Biopsies were obtained from 25 AAAs, 15 abdominal aortas, and 10 atherosclerotic thoracic aortas. IL-8 and MCP-1 expression was measured in homogenised specimens by ELISA. Infiltrate composition and localised expression of IL-8 and MCP-1 were determined through immunohistochemistry.. ELISA analysis demonstrated that IL-8 and MCP-1 were raised in the AAA compared to the controls [(IL-8, AAA vs. abdominal aorta: >28-fold, P<.001; AAA vs. thoracic aorta: >28-fold, P<.001) (MCP-1, AAA vs. abdominal aorta: 9-fold, P<.001; AAA vs. thoracic aorta: 19-fold, P<.001)]. Immunohistochemistry revealed that IL-8 was localised to the inflammatory infiltrate, which consisted predominantly of CD3(+) T- and CD20(+) B-lymphocytes. MCP-1 was predominantly expressed by CD68(+) macrophages. Increasing IL-8 expression was associated with an increase in mural inflammation, and an increase in CD3(+) T-lymphocytes of CD4(+) phenotype within the infiltrate population.. Pathways involving IL-8 and MCP-1 may be involved in AAA pathogenesis. IL-8 may be directly involved in the chemotaxis of T(H)-lymphocytes into the AAA wall.

Topics: Adult; Aged; Aortic Aneurysm, Abdominal; Chemokine CCL2; Female; Humans; Immunohistochemistry; Interleukin-8; Lymphocytes; Male; Middle Aged; Young Adult

Neutrophils/platelet interactions are involved in abdominal aortic aneurysm (AAA). The intraluminal thrombus (ILT) is a human model of platelet/neutrophil interactions. The present study focused on mediators involved in neutrophil recruitment in AAA.. Conditioned media from luminal, intermediate, and abluminal layers of 29 human ILTs were analysed for neutrophil markers [elastase/alpha1-antitrypsin and MMP9/NGAL complexes, myeloperoxidase (MPO), and alpha-defensin peptides], RANTES, platelet factor 4 (PF4), and interleukin-8 (IL-8). Their time-dependent release into serum from clots generated in vitro and their plasma concentrations in AAA patients and controls were determined. Immunohistochemistry for neutrophils, platelets, IL-8, PF4, and RANTES on AAA sections was performed; and molecules involved in ILT neutrophil chemotactic function were analysed in vitro. Neutrophils and platelets colocalized in the luminal layer of the thrombus. Consistently, neutrophil markers and platelet-derived RANTES and PF4 were released predominantly by the luminal thrombus pole, where their concentrations were significantly correlated. The luminal ILT layer was also the main source of IL-8, whose immunostaining colocalized with neutrophils. All were also released time dependently from clots and were increased in plasma of AAA patients. Luminal ILT layers displayed potent neutrophil chemotactic activity in vitro, which was inhibited by RANTES- and IL-8-blocking antibodies as well as by reparixin, an antagonist of the IL-8 receptors CXCR1 and CXCR2.. Taken together, these results suggest that platelet-derived RANTES and neutrophil-derived IL-8 are involved in attracting neutrophils to the luminal layer of AAA ILT.

Topics: Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Biomarkers; Case-Control Studies; Chemokine CCL5; Chemotaxis, Leukocyte; Culture Media, Conditioned; Humans; Interleukin-8; Male; Middle Aged; Neutrophil Infiltration; Platelet Factor 4

Epoxyeicosatrienoic acids (EETs) have been shown to have antiinflammatory effects and therefore may play a role in preventing vascular inflammatory and atherosclerotic diseases. Soluble epoxide hydrolase (s-EH) converts EETs into less bioactive dihydroxyeicosatrienoic acids. Thus, inhibition of s-EH can prevent degradation of EETs and prolong their effects. The present study aimed to test the hypothesis that inhibition of s-EH has vascular protective effects.. Six-month-old apolipoprotein E-deficient mice were chronically infused with angiotensin II (1.44 mg/kg/d) for 4 weeks to induce abdominal aortic aneurysm (AAA), accelerate atherosclerosis development and carotid artery ligation-induced vascular remodeling. The mice were treated with a novel s-EH inhibitor, AR9276 (1.5 g/L in drinking water) or vehicle for 4 weeks. The results demonstrated that AR9276 significantly reduced the rate of AAA formation and atherosclerotic lesion area, but had no effect on ligation-induced carotid artery remodeling. These effects were associated with a reduction of serum lipid, IL-6, murine IL-8-KC, and IL-1alpha, and downregulation of gene expressions of ICAM-1, VCAM-1, and IL-6 in the arterial wall.. The present data demonstrate that treatment with an s-EH inhibitor attenuates AAA formation and atherosclerosis development. The attendant downregulation of inflammatory mediators and lipid lowering effects may both contribute to the observed vascular protective effects.

Topics: Administration, Oral; Angiotensin II; Animals; Aortic Aneurysm, Abdominal; Apolipoproteins E; Atherosclerosis; Biological Availability; Carotid Arteries; Cholesterol; Disease Models, Animal; Down-Regulation; Dyslipidemias; Enzyme Inhibitors; Epoxide Hydrolases; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-1alpha; Interleukin-6; Interleukin-8; Ligation; Male; Mice; Mice, Knockout; Vascular Cell Adhesion Molecule-1

Inflammation plays a key role in the pathogenesis of an AAA (abdominal aortic aneurysm); however, the nature of the inflammatory factors and cellular response(s) involved in AAA growth is controversial. In the present study, we set out to determine the aortic levels of inflammatory cytokines in relation to downstream inflammatory transcription factors and cellular responses. A comparison of AAA wall samples with atherosclerotic wall samples taken from the same aortic region allowed AAA-specific inflammatory parameters to be identified that distinguish AAAs from ASD (aortic atherosclerotic disease). RT-PCR (real-time PCR), ELISA, Western blotting and immunohistochemistry were combined to assess cytokines and transcription factors at the mRNA and protein level, and their activation status. Compared with ASD, inflammatory parameters associated with Th1-type [T-bet, IL (interleukin)-2, IFN-gamma (interferon-gamma), TNF-alpha (tumour necrosis factor-alpha), IL-1alpha and cytotoxic T-cells] and Th2-type [GATA3, IL-4, IL-10, IL-13 and B-cells] responses were all increased in AAA samples. Evaluation of major downstream inflammatory transcription factors revealed higher baseline levels of C/EBP (CCAAT/enhancer-binding protein) alpha, beta and delta in the AAA samples. Baseline p65 NF-kappaB (nuclear factor kappaB) and c-Jun [AP-1 (activator protein-1)] levels were comparable, but their activated forms were strongly increased in the AAA samples. Downstream target genes of p65 NF-kappaB, c-Jun, IL-6 and IL-8 were hyperexpressed. Molecular and cellular processes associated with IL-6 and IL-8 hyperactivation were enhanced in the AAA samples, i.e. the expression of phospho-STAT-3 (signal transducer and activator of transcription-3) and perforin were elevated, and the content of plasma cells, neutrophils and vasa vasorum was increased. In conclusion, our findings demonstrate that an AAA is a general inflammatory condition which is characterized by enhanced expression and activation of pro-inflammatory transcription factors, accompanied by IL-6 and IL-8 hyperexpression and exaggerated downstream cellular responses, which together clearly distinguish an AAA from ASD.

Topics: Aged; Aortic Aneurysm, Abdominal; Aortic Valve Stenosis; Atherosclerosis; Biomarkers; Diagnosis, Differential; Female; Gene Expression Profiling; Humans; Inflammation Mediators; Interleukin-6; Interleukin-8; Male; Middle Aged; Reverse Transcriptase Polymerase Chain Reaction; Th1 Cells; Th2 Cells; Transcription Factors

The objective of this study is to evaluate the inflammatory response caused by endovascular stents in the treatment of aortic aneurysms.. Twenty-five patients underwent endovascular stent treatment from March through December 2005. The evolution of mediators (sedimentation velocity, C reactive protein, interleukin-6, interleukin-8, tumor necrosis factor-alpha, intercellular adhesion molecule-1, l-selectin), inflammatory cells (leukocytes, lymphocytes, platelets), serum creatinine and body temperature within preoperative period and in the following postoperative periods--1, 6, 24 and 48 h, 7 days, 1-3 months, was analyzed. In order to achieve statistic significance, Friedman test and Wilcoxon test were used, with index of significance of 5% (p<0.05).. Peak values of sedimentation velocity, C reactive protein and interleukin-6 were observed at 7 days (p<0.0001), 48 h (p<0.0001) and 24h (p<0.0001), respectively. Tumor necrosis factor-alpha and interleukin-8 did not show statistically significant variability during the entire follow-up. In terms of intercellular adhesion molecule-1 and l-selectin, their expressive values were found in late phase of follow-up, although without statistical significance. Elevation of leukocytes count occurred in premature phase of follow-up (p<0.0001), while lymphocyte and platelet count occurred in a late phase of follow-up (p<0.0001). Serum levels of creatinine did not show significant variability during follow-up. The period between 24 and 48 h corresponded to major frequency for fever (p<0.0001).. Individual mediators analysis and inflammatory cells demonstrated variability of their values during postoperative follow-up. This could help in the analysis of the inflammatory response evolution caused by endovascular stent treatment for aortic aneurysms in premature and late phases after implantation of the vascular prosthesis.

Topics: Adult; Aged; Aged, 80 and over; Aortic Aneurysm; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Blood Vessel Prosthesis Implantation; Female; Follow-Up Studies; Humans; Inflammation; Inflammation Mediators; Intercellular Adhesion Molecule-1; Interleukin-6; Interleukin-8; L-Selectin; Male; Middle Aged; Stents; Tumor Necrosis Factor-alpha

Although cytokines are known to be pivotal in the development of atherosclerotic diseases, few data exist regarding their expressions in the established stages such as aneurysmal or occlusive lesions. Therefore, in the present study the gene expression levels of cytokine-related substances in abdominal aortic aneurysm (AAA) and carotid artery stenosis (CAS) were determined using cDNA macroarray and real-time reverse transcriptase polymerase chain reaction (RT-PCR) methods.. Tissue samples were obtained from 31 patients with AAA and 24 with CAS. The array-specific [33P]-labeled cDNA probe mixture synthesized from 2.5 microg total RNA with gene-specific primers was hybridized with nylon membranes containing 375 cDNA clones. Densitometric analysis confirmed differences in expression (>5-fold) for 97 of the cytokine-related gene products between AAA and adjacent control tissue. Among these, simultaneous upregulation was found in the expression of interleukin (IL)-8 (9-fold) and its receptor, CXCR-2 (11-fold). Thus, the expressions of IL-8 and CXCR-2 were further quantified by real-time RT-PCR. The expression of both the genes was significantly upregulated in both AAA and CAS compared with control regions as followed: IL-8=0.53+/-0.16 vs 0.11+/-0.04 (p<0.01); CXCR-2=2.04+/-0.75 vs 0.29+/-0.10 (p<0.01) in AAA, and IL-8=1.35 +/-0.25 vs 0.60+/-0.16; CXCR-2=2.00 +/-0.51 vs 0.58+/-0.21 (p<0.05) in CAS. Under these conditions, the gene expressions of monocyte chemotactic protein-1 and its receptor, CCR-2, were not significantly different in the control and diseased regions of both AAA and CAS.. Sustained upregulation of IL-8 and CXCR-2 was observed in both AAA and CAS, suggesting the inflammatory process is still active in established dilated and occlusive atherosclerotic diseases. Whether upregulation of this system could be protective or not protective for disease development requires further study.

Topics: Aged; Aortic Aneurysm, Abdominal; Arterial Occlusive Diseases; Arteriosclerosis; Chemokines; Female; Gene Expression Profiling; Humans; Inflammation; Interleukin-8; Male; Oligonucleotide Array Sequence Analysis; Receptors, Chemokine; Receptors, Interleukin-8B; Reverse Transcriptase Polymerase Chain Reaction; Tissue Array Analysis; Up-Regulation

To determine whether surgical stress is less with transperitoneal or extraperitoneal abdominal aortic aneurysmectomy, blood concentrations of inflammatory cytokines and other inflammatory markers with recovery of bowel function were examined.. Patients who underwent abdominal aortic aneurysmectomy electively via the transperitoneal (T-group; n=15) or the extraperitoneal approach (E-group; n=17) were evaluated. Inflammatory cytokines (interleukin[IL]) IL-6, IL-8, C-reactive protein concentrations, and systemic inflammatory response syndrome score were determined before operation and after operation on days (POD) 1, 3, 7, and 14. Recovery of bowel function was estimated by the time taken for resumption of bowel movement and oral intake, and by the volume of fluid collection from the nasogastric tube.. Cytokine (IL-8) concentrations were higher in the T-group than the E-group with significant difference on POD 7 (4.8+/-0.5 versus 3.4+/-0.2 pg/mL, respectively; P=0.02). Recovery of bowel function and oral intake were earlier, and the volume of fluid collection from the nasogastric tube was smaller in the E-group than the T-group significantly.. Early recovery of bowel function and low concentration of inflammatory cytokines suggest that the extraperitoneal approach to the abdominal aorta is less stressful to the transperitoneal approach. Postoperative inflammatory response may mainly depend on damage of the bowel in the operation of the abdominal aortic aneurysm.

Topics: Adult; Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Biomarkers; C-Reactive Protein; Female; Gastrointestinal Motility; Humans; Inflammation; Interleukin-6; Interleukin-8; Intestinal Diseases; Male; Middle Aged; Peritoneum; Postoperative Complications; Recovery of Function; Retrospective Studies; Vascular Surgical Procedures

The purpose of this study was to semiquantify the magnitude of surgical stress in patients undergoing aortic surgery by measuring inflammatory responses perioperatively, focusing on cytokine secretion. Serum concentrations of interleukin (IL) 1alpha, IL-6, IL-8, and tumor necrotizing factor (TNF) Alpha were measured in patients undergoing abdominal or thoracic aortic aneurysmectomy preoperatively and periodically thereafter for 2 weeks. Urinary trypsin inhibitor (UTI/Cr) and C-reactive protein (CRP) concentration and the systemic inflammatory response syndrome (SIRS) score also were determined. Indices of inflammation and cytokine concentrations peaked at 1-3 days after surgery and decreased thereafter; however, IL-8 increased again after day 7. Concentrations of IL-8, UTI/Cr, and CRP and the SIRS score were still higher 14 days after surgery than preoperatively. The maximum concentrations of IL-6 and IL-8 were higher after thoracic than abdominal aortic repair; however, the maximum values of cytokines were not correlated with operative factors in all patients. A patient suffering from graft infection showed an increase in cytokine concentrations on day 7. The inflammatory response does not return to preoperative values within 2 weeks of surgery in patients undergoing thoracic or abdominal aortic aneurysm repair. The prolonged secretion of IL-8 suggests a host reaction to the synthetic prosthesis. A large increase in inflammatory cytokines on day 7 may indicate infection of the vascular graft.

Topics: Adult; Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Blood Vessel Prosthesis Implantation; C-Reactive Protein; Female; Glycoproteins; Humans; Interleukin-6; Interleukin-8; Interleukins; Male; Middle Aged; Postoperative Period; Stress, Physiological; Tumor Necrosis Factor-alpha

Cytosol levels of cytokines [interleukins 1b, 6, 8 (IL-1b, 6, 8), tumor necrosis factor-alpha (TNF-alpha)] in aneurysm walls were evaluated in a prospective non-randomized study of 57 patients. The group was divided into two subgroups: Subgroup I (ruptured aneurysms, n=11) and Subgroup II (asymptomatic aneurysms, n=32). A control group consisted of 14 kidney donors. Aortic walls were examined by immunohistochemistry and microscopy to detect inflammatory cells. More pronounced inflammatory changes and higher cytosol cytokine levels [IL6 (p<0.001), IL8 (p<0.0003) and TNFalpha (p<0.002)] were found in the walls of ruptured aneurysms than in the asymptomatic aneurysms. Immunohistochemically, most cells within the inflammatory infiltrates stained positively with the monoclonal antibody to the leucocyte common antigen (CD 45). The majority were of B-cell origin, which was demonstrated by positive staining with the monoclonal antibody L26 directed against the CD 20 antigen. These results show that an inflammatory process plays a significant role in patients with ruptured abdominal aortic aneurysms (AAA). A means of modifying the inflammatory process in the wall of AAAs might play an important role in preventing aneurysm rupture.

Topics: Aged; Aneurysm, Ruptured; Antibodies, Monoclonal; Antigens, CD20; Aortic Aneurysm, Abdominal; Cytokines; Female; Humans; Inflammation; Interleukin-6; Interleukin-8; Leukocyte Common Antigens; Male; Middle Aged; Plasma Cells; Prospective Studies; Tumor Necrosis Factor-alpha; Tunica Media

Pro- and anti-inflammatory cytokine release occurs with abdominal aortic aneurysm (AAA) repair although the relative contribution of each is currently poorly understood. Ischaemia-reperfusion injury is thought to play a greater role following open (OR) than endovascular (ER) repair, with resultant greater perioperative morbidity.. Thirty-two patients undergoing OR (n = 16) and ER (n = 16) of AAA were studied. Systemic venous (SV) blood was taken at induction (baseline), 0 h (last clamp off), 4, 24, 72 and 144 h, and femoral venous (FV) blood (indwelling catheter; lower torso venous effluent) at 0, 4 and 24 h. The cytokines interleukin (IL) 6, IL-8 and IL-10 were measured in these samples.. In OR, SV and FV IL-6 increased from baseline to a peak at 24 h (SV 589 pg/ml (P = 0.001 versus baseline) and FV 848 pg/ml (P = 0.05)) before declining at 144 h. In ER, there was a similar pattern but the increase was smaller (24 h: SV 260 pg/ml (P = 0.003 versus baseline) and FV 319 pg/ml (P = 0.06)) at all equivalent timepoints compared with OR. IL-8 peaked earlier (4 h) from baseline in both groups before declining by 144 h, and significant differences between SV and FV were seen only in the OR group. IL-10 levels peaked in both groups at 24 h before declining at 144 h, and there were no significant locosystemic differences between the groups.. Venous pro-inflammatory cytokine changes (IL-6) are consistent with significantly greater lower-torso reperfusion injury in patients undergoing OR. Smaller responses were seen after ER (IL-6 and IL-8), although both groups showed a similar anti-inflammatory response (IL-10); this pro- and anti-inflammatory imbalance may account for the increased morbidity associated with OR.

Topics: Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Endoscopy; Female; Humans; Inflammation; Interleukin-10; Interleukin-6; Interleukin-8; Male; Middle Aged

To compare the biological responses following an endoluminal repair and a conventional open repair of abdominal aortic aneurysm (AAA), 14 patients who underwent an endoluminal repair (endograft group) and 26 who underwent an open repair (open group) were investigated. As markers of biological responses, interleukin-6 (IL-6) and -8 (IL-8), granulocyte elastase (GEL), white blood cell count (WBC), and serum C-reactive protein (CRP) were all measured preoperatively as well as on postoperative days (POD) 1, 3, and 6. In addition, the blood loss, duration of surgery, initial oral intake the day after surgery, and length of hospital stay were compared between both groups. The plasma levels of IL-6, GEL, CRP, and WBC were higher in the endograft group than in the open group, while the CRP, WBC, and GEL levels all peaked on POD 3. The plasma level of IL-6 remained high in the endograft group, compared with that in the open group throughout the study period. Conversely, blood loss, initial oral intake the day after surgery, and the length of hospital stay were all significantly greater in the open group than in the endograft group, although there was no significant difference in the duration of surgery between the two groups. These findings indicate that although the endoluminal repair of AAA is supposed to be less invasive, the biological responses tend to be greater because of the manipulation related to the insertion of the stent graft.

Topics: Adult; Aged; Aged, 80 and over; Angioplasty; Aortic Aneurysm, Abdominal; Blood Vessel Prosthesis Implantation; C-Reactive Protein; Foreign-Body Reaction; Humans; Interleukin-6; Interleukin-8; Leukocyte Count; Leukocyte Elastase; Middle Aged; Stents

To determine the nature of and to compare the inflammatory responses induced by (1) endovascular and (2) conventional abdominal aortic aneurysm (AAA) repair.. Twelve consecutive patients undergoing elective infrarenal AAA repair were prospectively studied. Seven patients were selected for endovascular procedures (the EAAA group); five patients underwent open surgery (the OAAA group). Three control patients undergoing carotid thromboendarterectomy were also included. Serial peripheral venous blood samples were collected preoperatively, immediately after declamping or placement of the endograft, and at hours 1, 3, 6, 12, 24, 48, and 72. Acute phase response expression of peripheral T lymphocyte and monocyte activation markers and adhesion molecules (flow cytometry), soluble levels of cell adhesion molecules (enzyme-linked immunosorbent assay), cytokine (tumor necrosis factor alpha, interleukin-6, and interleukin-8) release (enzyme-linked immunosorbent assay), and liberation of complement products (nephelometry) were measured.. Regarding acute phase response, the EAAA and OAAA groups showed significant increases in C-reactive protein (P <.001 and P =.001), body temperature (P =.035 and P =.048), and leukocyte count (P <.001 and P <.001). Similar time course patterns were observed with respect to body temperature (P =.372). Statistically significant different patterns were demonstrated for C-reactive protein (P =.032) and leukocyte count (P =.002). Regarding leukocyte activation, a significant upregulation of peripheral T lymphocyte CD38 expression was observed in the OAAA group only (P =.001). Analysis of markers such as CD69, CD40L, CD25, and CD54 revealed no perioperative fluctuations in any group. Regarding circulating cell adhesion molecules, the EAAA and OAAA groups displayed significant increases in soluble intercellular adhesion molecule-1 (P =.003 and P =.001); there was no intergroup difference (P =.193). All groups demonstrated high soluble von Willebrand factor levels (P =.018, P =. 007, and P =.027), there being no differences in the patterns (P =. 772). Otherwise, soluble vascular cell adhesion molecule-1, soluble E-selectin, and soluble P-selectin did not appear to vary in any group. Regarding cytokine release, although a tendency toward high tumor necrosis factor alpha and interleukin-8 levels was noticed in the EAAA group, global time course effects failed to reach statistical significance (P =.543 and P =.080). In contrast, interleukin-6 showed elevations in all groups (P =.058, P <.001, and P =.004). Time course patterns did not differ between the EAAA and OAAA groups (P =.840). Regarding complement activation, the C3d/C3 ratio disclosed significant postoperative elevations in the EAAA and OAAA groups (P =.013 and P =.009). This complement product release was reduced in the EAAA group (P <.001).. The current study indicated that both endovascular and coventional AAA repair induced significant inflammatory responses. Our findings showed that there were no large differences between the procedures with respect to circulating cell adhesion molecule and cytokine release. Moreover, the endoluminal approach produced a limited response in terms of acute phase reaction, T lymphocyte activation, and complement product liberation. This might support the concept that endovascular AAA repair represents an attractive alternative to open surgery. Given the relatively small sample size, further larger studies are required for confirmation of our observations.

Topics: Aged; Aortic Aneurysm, Abdominal; Cell Adhesion Molecules; Complement System Proteins; Elective Surgical Procedures; Humans; Inflammation; Interleukin-6; Interleukin-8; Male; Middle Aged; Prospective Studies; T-Lymphocytes; Time Factors; Tumor Necrosis Factor-alpha; Vascular Surgical Procedures

To determine the inflammatory responses in endovascular abdominal aortic aneurysm (AAA) repair and their relation to clinical findings.. Prospective non-randomised study.. University Hospital, Department of Surgery.. Seven patients treated with an endoluminal procedure (AAA-E) and seven patients undergoing conventional surgery (AAA-C) were included. Inflammatory parameters were assessed by measurements of the cytokines interleukin (IL)-1 beta, IL-6, IL-8 and Tumour Necrosis Factor-alpha (TNF-alpha); analyses of complement proteins C1q, C4, C3, C5a and Terminal Complement Complexes (TCC); haematologic parameters and determination of C-reactive protein (CRP).. In six of seven patients in the AAA-E group blood pressure decreases were recorded during introduction of the device. IL-6 and CRP levels were found to be significantly higher in AAA-C patients compared to the AAA-E group. On the other hand, high TNF-alpha levels were recorded in the AAA-E group. Less consumption of the complement proteins C1q, C4 and C3 was observed in AAA-E compared to AAA-C patients. Increased C5a levels were recorded in the AAA-C group, whereas only slight fluctuations were noticed in the AAA-E group. TCC levels were unchanged in both groups.. Endovascular aortic aneurysm repair induced a significant inflammatory response, mainly involving TNF-alpha and differing from the findings during open AAA repair. These inflammatory responses were probably related to blood pressure decreases during the procedures. On the other hand, conventional repair induced responses related to the more extensive surgical trauma and reperfusion injury.

Topics: Aged; Aged, 80 and over; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Blood Pressure; Blood Vessel Prosthesis; C-Reactive Protein; Complement C1q; Complement C3; Complement C4; Complement C5a; Complement Membrane Attack Complex; Cytokines; Humans; Iliac Artery; Interleukin-1; Interleukin-6; Interleukin-8; Male; Middle Aged; Prospective Studies; Tumor Necrosis Factor-alpha

Angiogenesis, the growth and proliferation of blood vessels, may be important in the pathogenesis of atherosclerosis and thus in human atherosclerotic abdominal aortic aneurysms (AAAs). Endothelial migration or chemotaxis is a vital component of the angiogenic response. Here, human aortic endothelial cells (hAECs) were used to investigate the effect of AAA tissue supernatants on hAEC chemotaxis. AAA tissue conditioned media were found to be chemotactic for hAECs. We have previously shown that the angiogenic cytokines interleukin (IL)-8, and tumor necrosis factor (TNF)-alpha are present in AAAs and normal aortic explant conditioned media. Currently, we have found that basic fibroblast growth factor (bFGF) and platelet-derived growth factor can also be detected in these supernatants. In order to identify whether some of these soluble mediators contributed to the chemotactic activity of these supernatants, conditioned media were preincubated with either neutralizing anti-IL-8, anti-TNF-alpha, anti-bFGF antibodies or control serum. Anti-IL-8 and anti-TNF-alpha significantly inhibited AAA tissue supernatant-induced hAEC chemotaxis (p < 0.05), while anti-bFGF did not (p not significant). These results indicate that IL-8 and TNF-alpha may be important in chemotactic activity for hAECs in vitro and possibly in AAA neovascularization. The abrogation of angiogenesis using neutralizing antibodies may be a future goal in the therapy of certain disease states such as AAA where angiogenesis plays an important role.

Topics: Antibodies, Monoclonal; Aortic Aneurysm, Abdominal; Cell Movement; Cells, Cultured; Chemotaxis; Culture Media, Conditioned; Endothelium, Vascular; Enzyme-Linked Immunosorbent Assay; Fibroblast Growth Factor 2; Humans; Interleukin-8; Platelet-Derived Growth Factor; Tumor Necrosis Factor-alpha

Inflammatory leukocytes play a central role in the pathogenesis of human atherosclerotic disease, from early atherogenesis to the late stages of atherosclerosis, such as aneurysm formation. We have shown previously that human abdominal aortic aneurysms are characterized by the presence of numerous chronic inflammatory cells throughout the vessel wall (Am J Pathol 1990, 137: 1199-1213). The signals that attract lymphocytes and monocytes into the aortic wall in aneurysmal disease remain to be precisely defined. We have studied the production of the chemotactic cytokines interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) by aortic tissues obtained from 47 subjects. We compared the antigenic production of these cytokines by explants of: 1) human abdominal aneurysmal tissue, 2) occlusive (atherosclerotic) aortas, and 3) normal aortas. IL-8, which is chemotactic for neutrophils, lymphocytes, and endothelial cells was liberated in greater quantities by abdominal aortic aneurysms than by occlusive or normal aortas. Using immunohistochemistry, macrophages, and to a lesser degree endothelial cells, were found to be positive for the expression of antigenic IL-8. Similarly, MCP-1, a potent chemotactic cytokine for monocytes/macrophages, was released by explants from abdominal aortic aneurysms in greater quantities than by explants from occlusive or normal aortas. Using immunohistochemistry, the predominant MCP-1 antigen-positive cells were macrophages and to a lesser extent smooth muscle cells. Our results indicate that human abdominal aortic aneurysms produce IL-8 and MCP-1, both of which may serve to recruit additional inflammatory cells into the abdominal aortic wall, hence perpetuating the inflammatory reaction that may result in the pathology of vessel wall destruction and aortic aneurysm formation.

Topics: Aortic Aneurysm, Abdominal; Chemokine CCL2; Chemotactic Factors; Chemotaxis; Cytokines; Enzyme-Linked Immunosorbent Assay; Humans; Immunohistochemistry; Interleukin-8