Dataset Information

Increased expression and activation of absent in melanoma 2 inflammasome components in lymphocytic infiltrates of abdominal aortic aneurysms.

ABSTRACT: Chronic vascular inflammation is a key hallmark in the pathogenesis of abdominal aortic aneurysm (AAA). Recent investigations have suggested that the inflammasome, a cytosolic multiprotein complex that recognizes pathogen-associated molecular patterns, plays a role in atherosclerosis. However, its role in AAA inflammation has not yet been investigated. This pilot study analyzed inflammasome activation and its intramural localization in 24 biopsy samples from 11 patients with asymptomatic AAA versus 12 aortic samples from apparently healthy controls. Using a histological inflammation scale, we identified grade 2/3 inflammatory changes with lymphoid aggregates/tertiary lymphoid organs in 21 out of 24 AAA samples, whereas only 7 of the 12 control samples exhibited local grade 1 inflammatory changes. Strong expression levels of "apoptosis-associated speck-like protein with a caspase recruitment domain" (ASC), caspase-1, caspase-5 and "absent in melanoma 2" (AIM2) were detected by immunohistochemistry in both sporadic infiltrating lymphoid cells and lymphoid aggregates located in the outer media and adventitia of AAA samples. In contrast, inflammasome-positive cells were restricted to cholesterol plaque-associated areas and to single infiltrating cells in control aortas. Analysis of gene expression using real-time polymerase chain reaction (PCR) revealed significantly increased median mRNA levels of the inflammasome core components PYCARD (ASC), CASP1 (Caspase-1) and IL1B (IL-1?) in AAA tissue compared with normal aorta. Moreover, significantly increased median amounts of AIM2 protein and mature caspase-5 (p20) were found in samples associated with high rupture risk compared with paired low rupture risk samples of the same AAA patient. We conclude from our data that AAA-associated lymphoid cells are capable of inflammasome signaling, suggesting that inflammasome activation is involved in the chronic inflammatory process driving AAA progression.

SUBMITTER: Dihlmann S

PROVIDER: S-EPMC4069270 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Increased expression and activation of absent in melanoma 2 inflammasome components in lymphocytic infiltrates of abdominal aortic aneurysms.

Dihlmann Susanne S Erhart Philipp P Mehrabi Arianeb A Nickkholgh Arash A Lasitschka Felix F Böckler Dittmar D Hakimi Maani M

Molecular medicine (Cambridge, Mass.) 20140619

Chronic vascular inflammation is a key hallmark in the pathogenesis of abdominal aortic aneurysm (AAA). Recent investigations have suggested that the inflammasome, a cytosolic multiprotein complex that recognizes pathogen-associated molecular patterns, plays a role in atherosclerosis. However, its role in AAA inflammation has not yet been investigated. This pilot study analyzed inflammasome activation and its intramural localization in 24 biopsy samples from 11 patients with asymptomatic AAA ver ...[more]

PMID: 24618883

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Project description:Information about the tissue characteristics of abdominal aortic aneurysms (AAAs), some of which may be reflected in the serum, can help to elucidate AAA pathogenesis and identify new AAA biomarkers. This information would be beneficial not only for diagnostics and follow-up but also for potential therapeutic intervention. Therefore, the aim of our study was to compare the expression of structural proteins, immune factors (T and B lymphocytes, macrophages, neutrophils and pentraxin 3 (PTX3)), osteoprotegerin (OPG), microvessels and hypoxic cells in AAA and nonaneurysmal aortic walls. We examined specimens collected during surgery for AAA repair (n = 39) and from the abdominal aortas of kidney donors without AAA (n = 8). Using histochemical and immunohistochemical methods, we quantified the areas positive for smooth muscle actin, desmin, elastin, collagen, OPG, CD3, CD20, MAC387, myeloperoxidase, PTX3, and hypoxia-inducible factor 1-alpha and the density of CD31-positive microvessels. AAA samples contained significantly less actin, desmin, elastin and OPG, more collagen, macrophages, neutrophils, T lymphocytes, B lymphocytes, hypoxic cells and PTX3, and a greater density of vasa vasorum (VV) than those in non-AAA samples. Hypoxia positively correlated with actin and negatively correlated with collagen. Microvascular density was related to inflammatory cell infiltrates, hypoxia, PTX3 expression and AAA diameter. The lower OPG expression in AAAs supports the notion of its protective role in AAA remodeling. AAA contained altered amounts of structural proteins, implying reduced vascular elasticity. PTX3 was upregulated in AAA and colocalized with inflammatory infiltrates. This evidence supports further evaluation of PTX3 as a candidate marker of AAA. The presence of aortic hypoxia, despite hypervascularization, suggests that hypoxia-induced neoangiogenesis may play a role in AAA pathogenesis. VV angiogenesis of the AAA wall increases its vulnerability.

Project description:BACKGROUND:An abdominal aortic aneurysm (AAA) is an abnormal ballooning of the major abdominal artery. Some AAAs present as emergencies and require surgery; others remain asymptomatic. Treatment of asymptomatic AAAs depends on many factors but an important one is size of the aneurysm, as risk of rupture increases with aneurysm size. Large asymptomatic AAAs (> 5.5 cm in diameter) are usually operated on; very small AAAs (< 4.0 cm diameter) are monitored with ultrasonography. The optimal timing of surgery would benefit from further evidence. OBJECTIVES:This review compared long-term survival in patients with AAAs of diameter 4.0 to 5.5 cm who received immediate repair versus routine ultrasound surveillance. SEARCH METHODS:For this update the Cochrane Peripheral Vascular Diseases Group searched their Specialised Register (February 2012) and CENTRAL (2012, Issue 1). Reference lists of relevant articles were checked for additional studies and the searches were supplemented by handsearches of recent conference proceedings and information from experts in the field. SELECTION CRITERIA:Randomised controlled trials in which men and women with asymptomatic AAAs of diameter 4.0 to 5.5 cm were randomly allocated to immediate repair or imaging-based surveillance at least every six months. Outcomes had to include mortality or survival. DATA COLLECTION AND ANALYSIS:Two authors (GF, MAMM) abstracted the data, which were cross-checked by the other authors (DJB, JTP). Due to the small number of trials, formal tests of heterogeneity and sensitivity analyses were not conducted. MAIN RESULTS:Four trials with a combined total of 3314 patients, the UK Small Aneurysm Trial (UKSAT), the Aneurysm Detection and Management (ADAM) trial, the Comparison of Surveillance Versus Aortic Endografting for Small Aneurysm Repair (CAESAR), and the Positive Impact of Endovascular Options for treating Aneurysms Early (PIVOTAL) fulfilled the inclusion criteria. The four trials showed an early survival benefit in the surveillance group (due to 30-day operative mortality with surgery) but no significant differences in long-term survival (adjusted hazard ratio (HR) 0.88, 95% confidence interval (CI) 0.75 to 1.02, mean follow up 10 years (UKSAT); HR 1.21, 95% CI 0.95 to 1.54, mean follow up 4.9 years (ADAM); HR 0.76, 95% CI 0.30 to 1.93, median follow up 32.4 months (CAESAR); HR 1.01, 95% CI 0.49 to 2.07, mean follow up 20 months (PIVOTAL)). The meta analyses of mortality at one year (CAESAR and PIVOTAL only) and six years (UKSAT and ADAM only) revealed a non-significant association (Peto odds ratio at one year 1.15, 95% CI 0.59 to 2.25; Peto odds ratio at six years 1.11, 95% CI 0.91 to 1.34). AUTHORS' CONCLUSIONS:The results from the four trials to date demonstrate no advantage to early repair (via open or endovascular surgery) for small AAA (4.0 to 5.5 cm) and suggest that 'best care' for these patients favours surveillance. Furthermore, the more recent trials focused on the efficacy of endovascular aneurysm repair and still failed to show benefit. Thus, both open and endovascular repair of small AAAs are not supported by currently available evidence.

Project description:Background Abdominal aortic aneurysm has become increasingly important owing to demographic changes. Some other diseases, for example, cholecystolithiasis, chronic obstructive pulmonary disease, and hernias, seem to co-occur with abdominal aortic aneurysm. The aim of this retrospective analysis was to identify new comorbidities associated with abdominal aortic aneurysm.Methods We compared 100 patients with abdominal aortic aneurysms and 100 control patients. Their preoperative computed tomographic scans were examined by two investigators independently, for the presence of hernias, diverticulosis, and cholecystolithiasis. Medical records were also reviewed. Statistical analysis was performed using univariate analysis and multiple logistic regression analysis.Results The aneurysm group had a higher frequency of diverticulosis (p = 0.008). There was no significant difference in the occurrence of hernia (p = 0.073) or cholecystolithiasis (p = 1.00). Aneurysm patients had a significantly higher American Society of Anesthesiology score (2.84 vs. 2.63; p = 0.015) and were more likely to have coronary artery disease (p < 0.001), congestive heart failure (p < 0.001), or chronic obstructive pulmonary disease (p < 0.001). Aneurysm patients were more likely to be former (p = 0.034) or current (p = 0.006) smokers and had a significantly higher number of pack years (p < 0.001). Aneurysm patients also had a significantly poorer lung function. In multivariate analysis, the following factors were associated with aneurysms: chronic obstructive pulmonary disease (odds ratio, OR = 12.24; p = 0.002), current smoking (OR = 4.14; p = 0.002), and coronary artery disease (OR = 2.60; p = 0.020).Conclusions Our comprehensive analysis identified several comorbidities associated with abdominal aortic aneurysms. These results could help to recognize aneurysms earlier by targeting individuals with these comorbidities for screening.

Dataset Information

Increased expression and activation of absent in melanoma 2 inflammasome components in lymphocytic infiltrates of abdominal aortic aneurysms.

Publications

Increased expression and activation of absent in melanoma 2 inflammasome components in lymphocytic infiltrates of abdominal aortic aneurysms.

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