Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0162871 (abdominal aortic aneurysm)
 8,664 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mouse resident peritoneal M phi release AAA and metabolize it into cyclooxygenase- and lipoxygenase-derived eicosanoids, when triggered in vitro with different stimuli. Pretreatment of M phi with nonimmune IFN-alpha and IFN-beta dramatically decreased AA liberation from M phi phospholipids and eicosanoid formation after stimulation of M phi with Zy, A23187, or PMA. M phi exposed to immune IFN-gamma also showed a substantial impairment of both AA liberation and eicosanoid production upon exposure to Zy. However, AA and eicosanoid release was increased by IFN-gamma, rather than depressed, in PMA-triggered M phi. In addition, IFN-gamma showed differential effects on M phi stimulated with A23187. In fact, it inhibited AA release as well as formation of lipoxygenase-derived LTC4, but it highly increased the release of the cyclooxygenase products PGE2 and 6-keto PGF1 alpha. The ability of IFN-gamma to differentially modulate AA metabolism of M phi, depending on the nature of the triggering agent, sets forth the high specificity of the regulatory capacity of this molecule. This is at variance with the down regulation of AA metabolism that is generally observed with nonimmune IFN.
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PMID:Regulation of arachidonic acid metabolism in macrophages by immune and nonimmune interferons. 392 10

The expression of the previously uncharacterized gene Adir (for ATP dependent interferon responsive gene) was increased by 5- to 15-fold in tissue of the oral cavity or in spleen and liver of mice treated orally or intraperitoneally with IFN-alpha, and in mouse cells treated in vitro with IFN-alpha or IFN-gamma. The level of Adir mRNA was also increased 20- to 40-fold in the brains of animals infected with encephalomyocarditis virus. Adir is expressed ubiquitously in mouse tissues as 1.9-, 2.4-, and 3.5-kb mRNA transcripts encoding a 385-amino-acid protein with a conserved ATP binding domain containing typical nucleotide and Mg(2+) binding sites. We also characterized the human ortholog, ADIR, which is located on chromosome 1q25-q31 and contains six exons encoding a 397-amino-acid protein with 80% homology to the mouse protein. A single 2.3-kb mRNA was detected in all human tissues examined, except for placenta, which also contained a 1.25-kb tissue-specific transcript generated by alternative splicing and encoding a putative 336-amino-acid protein. Although ADIR exhibits low homology to DYT1 and TOR1B, the deduced ADIR protein sequences are highly homologous to torsin A and torsin B and more distantly related to members of the Clp/HSP100 family of proteins, suggesting that ADIR, like torsins, is related to the AAA chaperone-like family of ATPases. An ADIR-EGFP fusion protein expressed in HeLa cells was shown to be associated with the endoplasmic reticulum.
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PMID:Molecular cloning of ADIR, a novel interferon responsive gene encoding a protein related to the torsins. 1186 61

The aim of our study was to evaluate the frequency of C. pneumoniae infection in abdominal aortic aneurysm (AAA) patients by measuring C. pneumoniae specific serum IgG, IgM and IgA levels and the activation of their immune system by measuring the concentrations of IL-10, IL-12, IFN-gamma and TNF-alpha in patients' serum. Microimmunofluorescence method was applied to evaluate the level of anti-C. pneumoniae IgG, IgA and IgM. The concentrations of cytokines were evaluated using ELISA method. Serologic markers of persistent C. pneumoniae infection have been detected in 25/28 (89.3%) patients and in 6/20 (30%) healthy controls. In 40% (10/25) of patients with serologic markers of persistent C. pneumoniae infection high titers of specific IgG and IgA indicated active infection--reinfection or exacerbation of chronic infection. Mean concentrations of IL-10, IL-12, IFN-gamma and TNF-alpha indicated lack of protection against intracellular pathogens. Since all patients in this group were diagnosed as having symptomatic AAA, we suggest that active infection can exacerbate inflammation in the AAA wall and accelerate progression of the disease. In our opinion patients with active C. pneumoniae infection may be candidates to the antimicrobial treatment.
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PMID:[The relation between Chlamydia pneumoniae infection and abdominal aortic aneurysm]. 1189 45

Abdominal aortic aneurysm (AAA) is one of a number of diseases associated with a prominent inflammatory cell infiltrate and local destruction of structural matrix macromolecules. This inflammatory infiltrate is predominately composed of T lymphocytes and macrophages. Delineating specific contribution of these inflammatory cells and their cytokines in AAA formation is the key to understanding AAA and other chronic inflammatory disease processes. Our previous studies have demonstrated that macrophages are the major source of matrix metalloproteinase-9, which is required for aneurysmal degeneration in the murine AAA model. However, the role of CD4(+) T cells, the most abundant infiltrates in aneurysmal aortic tissue, is uncertain. In the present study, we found that in the absence of CD4(+) T cells, mice are resistant to aneurysm induction. Previous studies have shown that IFN-gamma levels are increased in AAA. IFN-gamma is a main product of T cells. Intraperitoneal IFN-gamma was able to partially reconstitute aneurysms in CD4(-/-) mice. Furthermore, mice with a targeted deletion of IFN-gamma have attenuation of MMP expression and inhibition of aneurysm development. Aneurysms in IFN-gamma(-/-) mice can be reconstituted by reinfusion of competent splenocytes from the corresponding wild-type mice. This study demonstrates the pivotal role that T cells and the T cell cytokine, IFN-gamma, play in orchestrating matrix remodeling in AAA. This study has important implications for other degenerative diseases associated with matrix destruction.
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PMID:Key roles of CD4+ T cells and IFN-gamma in the development of abdominal aortic aneurysms in a murine model. 1476 34

Abdominal aortic aneurysms (AAAs) cause death due to complications related to expansion and rupture. The underlying mechanisms that drive AAA development remain largely unknown. We recently described evidence for a shift toward T helper type 2 (Th2) cell responses in human AAAs compared with stenotic atheromas. To evaluate putative pathways in AAA formation, we induced Th1- or Th2-predominant cytokine environments in an inflammatory aortic lesion using murine aortic transplantation into WT hosts or those lacking the receptors for the hallmark Th1 cytokine IFN-gamma, respectively. Allografts in WT recipients developed intimal hyperplasia, whereas allografts in IFN-gamma receptor-deficient (GRKO) hosts developed severe AAA formation associated with markedly increased levels of MMP-9 and MMP-12. Allografts in GRKO recipients treated with anti-IL-4 antibody to block the characteristic IL-4 Th2 cytokine or allografts in GRKO hosts also congenitally deficient in IL-4 did not develop AAA and likewise exhibited attenuated collagenolytic and elastolytic activities. These observations demonstrate an important dichotomy between cellular immune responses that induce IFN-gamma- or IL-4-dominated cytokine environments. The findings establish important regulatory roles for a Th1/Th2 cytokine balance in modulating matrix remodeling and have important implications for the pathophysiology of AAAs and arteriosclerosis.
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PMID:Th2-predominant inflammation and blockade of IFN-gamma signaling induce aneurysms in allografted aortas. 1525 83

Immune cell infiltration, vascular smooth muscle cell (VSMC) proliferation, and apoptosis are pathological hallmarks of atherosclerosis. The multifocal, chronic, and inflammatory nature of this disease of the cardiovascular system complicates targeted cellular therapy and emphasizes the need to understand the role and interaction of immune cells with VSMCs. We characterized the immune cell subsets present in human atherosclerotic tissue derived from atherosclerotic abdominal aortic aneurysm (AAA) and expanded them to study their interaction with autologous plaque-derived VSMCs in vitro. We show here that apart from T lymphocytes, plaque infiltrates consist of lots of NK cells and significant proportions of NKT cells that express T cell receptor (TCR) alphabeta, CD4, and the NK markers CD56 and CD161. The infiltrates are predominantly IFN-gamma-producing Type 1 lymphoid cells. When cocultured, the T and NKT cells adhere to VSMCs. CD4+ T cells enhance VSMC proliferation. VSMCs in turn enhance CD4+CD161+ NKT but not CD4+ or CD8+ T cell proliferation. CD4+CD161+ NKT cells inhibit VSMC proliferation by inducing apoptosis. Our results suggest that the interactions of Type 1 CD4+ T and CD4+CD161+ NKT cells with VSMCs may regulate VSMC proliferation and death respectively in atherosclerosis and the balance of these interactions could determine plaque stability.
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PMID:Atherosclerotic abdominal aortic aneurysm and the interaction between autologous human plaque-derived vascular smooth muscle cells, type 1 NKT, and helper T cells. 1573 63

The functional repertoire of T cells in abdominal aortic aneurysm (AAA) and the exact nature of aortic wall adaptive cellular immune responses still remains a matter of debate. In this study, we sought to determine whether type 1 or type 2 responses occur predominantly in human aneurysmal aortic lesions. We first examined the phenotype and cytokine secretion profile of T lymphocytes freshly isolated from aneurysmal aortic wall for comparison with their circulating counterparts using flow cytometry. We found that both populations of infiltrating CD4(+) and CD8(+)T cells displayed a unique activated memory phenotype. In addition, we identified the presence in human aneurysmal aortic lesion of CD4(+)T cells producing high levels of interferon (IFN)-gamma but not interleukin (IL)-4, reflecting their type 1 nature. Quantitative analysis of cytokine gene expression confirmed increased IFN-gamma transcript levels in infiltrating cells compared to controls. We next analysed aortic wall responses using LightCycler-based quantitative real-time reverse transcription-polymerase chain reaction. Compared to control non-diseased aortic samples, we demonstrated that whole AAA tissues exhibited high mRNA levels of IFN-gamma but not IL-4. Overexpression of the transcription factor T-bet in the absence of significant GATA-3 expression further assessed the type 1 polarization of aortic wall immune responses. These findings indicate that type 1 CD4(+)T cells predominate in human AAA lesions. This study has important implications for the pathogenesis of aneurysm disease. Through the production of IFN-gamma, T cells may indeed contribute to orchestrate extracellular matrix remodelling.
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PMID:Predominance of type 1 CD4+ T cells in human abdominal aortic aneurysm. 1629 65

Abdominal aortic aneurysm (AAA), an inflammatory disease, involves leukocyte recruitment, immune responses, inflammatory cytokine production, vascular remodeling, neovascularization, and vascular cell apoptosis, all of which contribute to aortic dilatation. This study demonstrates that mast cells, key participants in human allergic immunity, participate in AAA pathogenesis in mice. Mast cells were found to accumulate in murine AAA lesions. Mast cell-deficient KitW-sh/KitW-sh mice failed to develop AAA elicited by elastase perfusion or periaortic chemical injury. KitW-sh/KitW-sh mice had reduced aortic expansion and internal elastic lamina degradation; decreased numbers of macrophages, CD3+ T lymphocytes, SMCs, apoptotic cells, and CD31+ microvessels; and decreased levels of aortic tissue IL-6 and IFN-gamma. Activation of mast cells in WT mice via C48/80 injection resulted in enhanced AAA growth while mast cell stabilization with disodium cromoglycate diminished AAA formation. Mechanistic studies demonstrated that mast cells participated in angiogenesis, aortic SMC apoptosis, and matrix-degrading protease expression. Reconstitution of KitW-sh/KitW-sh mice with bone marrow-derived mast cells from WT or TNF-alpha-/- mice, but not from IL-6-/- or IFN-gamma-/- mice, caused susceptibility to AAA formation to be regained. These results demonstrate that mast cells participate in AAA pathogenesis in mice by releasing proinflammatory cytokines IL-6 and IFN-gamma, which may induce aortic SMC apoptosis, matrix-degrading protease expression, and vascular wall remodeling, important hallmarks of arterial aneurysms.
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PMID:Mast cells modulate the pathogenesis of elastase-induced abdominal aortic aneurysms in mice. 1793 68

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.
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PMID:Enhanced expression and activation of pro-inflammatory transcription factors distinguish aneurysmal from atherosclerotic aorta: IL-6- and IL-8-dominated inflammatory responses prevail in the human aneurysm. 1807 85

This is a study to define the profile of chemokine receptors expressed on isolated infiltrating lymphocytes in human abdominal aortic aneurysms (AAAs), and to examine their role in lymphoid recruitment. AAA T-lymphocytes were CXCR4-positive, CCR7-negative and partially CXCR3 and CCR5-positive. Functionally, AAA T-cells were proinflammatory effector cells, as they produced IFN-gamma and granzyme A. AAA B-lymphocytes were CXCR4-positive and exhibited low CXCR5 expression. A relevant feature of infiltrating T- and B-lymphocytes was the high intensity of CXCR4 expression and the capability to migrate to CXCL12. CXCL12-producing cells were found in the adventitia of AAA. These cells were CD45-negative and partially VCAM-1 and DR-positive. In summary, the present results suggest that CXCR4, expressed on infiltrating lymphocytes, and CXCL12, expressed on stromal cells, is involved in the recruitment of lymphocytes within the arterial wall in AAA.
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PMID:Chemokine receptor expression on infiltrating lymphocytes from abdominal aortic aneurysms: role of CXCR4-CXCL12 in lymphoid recruitment. 1828 Oct 50


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