RESUMO
The pathogenesis of the aortic aneurysm (AA) includes several mechanisms, such as chronic sterile inflammation and homeostasis imbalance, with arteriosclerosis, hemodynamic forces, and genetic factors. In addition to the roles of these processes in the development of AA, neutrophilic activity may play a pivotal role (mostly in inflammation and thrombus formation). Neutrophils, which play a crucial role in innate immunity, can release neutrophil extracellular traps (NETs), one of the mechanisms against fighting pathogens, beside phagocytosis and degranulation. NETs are structures composed of nuclear elements (eg, chromatin and modified histones) and granular and cytoplasmic components, which can lead to inflammation and coagulation changes. In addition, the exacerbation of NETosis (the process of NET formation) can be noticed in vascular diseases, including in the development of AA and myocardial infarction and in diabetes, hypertension, and COPD, which are the risk factors of the presence of AA. The discharge of NETs, which are extracellular materials formed by citrullinated histones (Cit-H), cell-free DNA fibers (cf-DNA), and granular and cytoplasmic molecules, is a newly identified method of neutrophil activation that can be activated by endogenous inflammatory stimuli, which contribute to AA development. Cit-H and cf-DNA can be used as biomarkers of AA growth. By understanding the neutrophilic influence of NET release, a new pathway of screening AA growth (by measurement of biomarkers of NETosis) and pharmacological assessment (by repression of NET formation) can be developed. This review summarizes the current knowledge about the influence of NETs on AA growth in human and animal studies.
Assuntos
Aneurisma Aórtico/imunologia , Aterosclerose/imunologia , Armadilhas Extracelulares/imunologia , Inflamação/imunologia , Neutrófilos/imunologia , Trombose/imunologia , Animais , Aterosclerose/fisiopatologia , Endotélio Vascular/fisiopatologia , Humanos , Inflamação/fisiopatologia , Trombose/fisiopatologiaRESUMO
BACKGROUND: Acute type A aortic dissection (ATAAD) is one of the most lethal cardiovascular diseases, and its molecular mechanism remains unclear. METHODS: Differentially expressed genes (DEGs) between ATAAD and control were detected by limma R package in GSE52093, GSE153434, GSE98770, and GSE84827, respectively. The coexpression network of DEGs was identified by the WGCNA package. Enrichment analysis was performed for module genes that were positively correlated with ATAAD using clusterProfiler R package. In addition, differentially methylated markers between aortic dissection and control were identified by ChAMP package. After comparing with ATAAD-related genes, a protein-protein interaction (PPI) network was established based on the STRING database. The genes with the highest connectivity were identified as hub genes. Finally, differential immune cell infiltration between ATAAD and control was identified by ssGSEA. RESULTS: From GSE52093 and GSE153434, 268 module genes were obtained with consistent direction of differential expression and high correlation with ATAAD. They were significantly enriched in T cell activation, HIF-1 signaling pathway, and cell cycle. In addition, 2060 differentially methylated markers were obtained from GSE84827. Among them, 77 methylation markers were ATAAD-related DEGs. Using the PPI network, we identified MYC, ITGA2, RND3, BCL2, and PHLPP2 as hub genes. Finally, we identified significantly differentially infiltrated immune cells in ATAAD. CONCLUSION: The hub genes we identified may be regulated by methylation and participate in the development of ATAAD through immune inflammation and oxidative stress response. The findings may provide new insights into the molecular mechanisms and therapeutic targets for ATAAD.
Assuntos
Aneurisma Aórtico/genética , Dissecção Aórtica/genética , Redes Reguladoras de Genes , Doença Aguda , Dissecção Aórtica/imunologia , Aneurisma Aórtico/imunologia , Estudos de Casos e Controles , Biologia Computacional , Metilação de DNA/genética , Bases de Dados Genéticas , Perfilação da Expressão Gênica , Marcadores Genéticos , Humanos , Mapas de Interação de Proteínas/genéticaRESUMO
OBJECTIVES: The 2019 ACR/EULAR classification criteria for IgG4-related disease (IgG4-RD) have exclusion criteria including positive disease-specific autoantibodies, and these have been documented to have a high specificity. This study aimed to further validate these criteria as well as identify characteristics of patients showing false-negative results. METHODS: We retrospectively analysed 162 IgG4-RD patients and 130 mimickers. The sensitivity, specificity and fulfilment rates for each criterion were calculated, and intergroup comparisons were performed to characterize the false-negative cases. RESULTS: Both the IgG4-RD patients and mimickers were aged ≥65 years with male predominance. The final diagnoses of mimickers were mainly malignancy, vasculitis, sarcoidosis and aneurysm. The classification criteria had a sensitivity of 72.8% and specificity of 100%. Of the 44 false-negative cases, one did not fulfil the entry criteria, 20 fulfilled one exclusion criterion and 27 did not achieve sufficient inclusion criteria scores. The false-negative cases had fewer affected organs, lower serum IgG4 levels, and were less likely to have received biopsies than the true-positive cases. Notably, positive disease-specific autoantibodies were the most common exclusion criterion fulfilled in 18 patients, only two of whom were diagnosed with a specific autoimmune disease complicated by IgG4-RD. In addition, compared with the true-positive cases, the 18 had comparable serum IgG4 levels, number of affected organs, and histopathology and immunostaining scores despite higher serum IgG and CRP levels. CONCLUSIONS: The ACR/EULAR classification criteria for IgG4-RD have an excellent diagnostic specificity in daily clinical practice. Positive disease-specific autoantibodies may have limited clinical significance for the diagnosis of IgG4-RD.
Assuntos
Autoanticorpos/imunologia , Doença Relacionada a Imunoglobulina G4/diagnóstico , Idoso , Anticorpos Antiproteína Citrulinada/imunologia , Anticorpos Anticitoplasma de Neutrófilos/imunologia , Anticorpos Antinucleares/imunologia , Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/imunologia , Doenças da Aorta/diagnóstico , Doenças da Aorta/imunologia , Aortite/diagnóstico , Aortite/imunologia , Hiperplasia do Linfonodo Gigante/diagnóstico , Hiperplasia do Linfonodo Gigante/imunologia , Dacriocistite/diagnóstico , Dacriocistite/imunologia , Diagnóstico Diferencial , Reações Falso-Negativas , Feminino , Humanos , Doença Relacionada a Imunoglobulina G4/imunologia , Nefropatias/diagnóstico , Nefropatias/imunologia , Linfoma/diagnóstico , Linfoma/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/imunologia , Pancreatopatias/diagnóstico , Pancreatopatias/imunologia , Pancreatite/diagnóstico , Pancreatite/imunologia , Estudos Retrospectivos , Doenças das Glândulas Salivares/diagnóstico , Doenças das Glândulas Salivares/imunologia , Sarcoidose/diagnóstico , Sarcoidose/imunologia , Sialadenite/diagnóstico , Sialadenite/imunologiaRESUMO
Acute aortic syndrome is a group of interlinked conditions with common presenting symptoms, including aortic dissection, penetrating atherosclerotic ulcer, and intramural hematoma. Pharmacological management of acute aortic syndrome is a growing area, with key themes to address the underlying inflammatory pathways believed to be the cause. Research into interleukins, matrix metalloproteinases, and granulocyte macrophage colony-stimulating factor are just some of the many immunological properties being investigated and translated into medical therapies. Stem cell experiments may indicate further advances in the pathologies of acute aortic syndrome. The study of pharmacogenomics to improve treatment across different genomes is also a novel area outlined in this paper.
Assuntos
Aneurisma Aórtico/terapia , Dissecção Aórtica/terapia , Hematoma/terapia , Fatores Imunológicos/uso terapêutico , Imunoterapia , Transplante de Células-Tronco , Úlcera/terapia , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/genética , Dissecção Aórtica/imunologia , Aneurisma Aórtico/diagnóstico por imagem , Aneurisma Aórtico/genética , Aneurisma Aórtico/imunologia , Hematoma/diagnóstico por imagem , Hematoma/genética , Hematoma/imunologia , Humanos , Fatores Imunológicos/efeitos adversos , Transplante de Células-Tronco/efeitos adversos , Síndrome , Úlcera/diagnóstico por imagem , Úlcera/genética , Úlcera/imunologiaRESUMO
Saprochaete species infection is a rare fungal disease reported so far only in immunocompromised patients. We describe the first case of aortitis caused by Saprochaete capitata, presenting as ascending aorta aneurysm, with secondary endophthalmitis in an immunocompetent patient. Infection by Saprochaete capitata is potentially fatal, with a mortality ranging from 50% to 90% of cases. In the present case aortic aneurysm caused by Saprochaete capitata aortitis was successfully treated by the combination of accurate diagnosis with surgical and specific antifungal therapy.
Assuntos
Aneurisma Infectado/microbiologia , Aneurisma Aórtico/microbiologia , Aortite/microbiologia , Imunocompetência , Infecções Fúngicas Invasivas/microbiologia , Revascularização Miocárdica/efeitos adversos , Saccharomycetales/isolamento & purificação , Idoso , Aneurisma Infectado/diagnóstico , Aneurisma Infectado/imunologia , Aneurisma Infectado/terapia , Antibacterianos/uso terapêutico , Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/imunologia , Aneurisma Aórtico/terapia , Aortite/diagnóstico , Aortite/imunologia , Aortite/terapia , Implante de Prótese Vascular , Humanos , Infecções Fúngicas Invasivas/diagnóstico , Infecções Fúngicas Invasivas/imunologia , Infecções Fúngicas Invasivas/terapia , Masculino , Saccharomycetales/efeitos dos fármacos , Saccharomycetales/imunologia , Resultado do TratamentoRESUMO
Kawasaki disease (KD) is a medium vessel vasculitis that affects young children. Despite extensive research over the last 50 years, the etiology of KD remains an enigma. Seasonal change in wind patterns was shown to have correlation with the epidemics of KD in Japan. Occurrence of disease in epidemiological clusters, seasonal variation, and a very low risk of recurrence suggest that KD is triggered by an infectious agent. The identification of oligoclonal IgA response in the affected tissues suggests an antigen-driven inflammation. The recent identification of a viral antigen in the cytoplasm of bronchial ciliated epithelium also favors infection as the main trigger for KD. Pointers that suggest a genetic basis of KD include a high disease prevalence in North-East Asian populations, a high risk among siblings, and familial occurrence of cases. Dysregulated innate and adaptive immune responses are evident in the acute stages of KD. In addition to the coronary wall inflammation, endothelial dysfunction and impaired vascular remodeling contribute to the development of coronary artery abnormalities (CAAs) and thrombosis. Genetic aberrations in certain intracellular signaling pathways involving immune effector functions are found to be associated with increased susceptibility to KD and development of coronary artery abnormalities (CAAs). Several susceptible genes have been identified through genome-wide association studies (GWAS) and linkage studies (GWLS). The genes that are studied in KD can be classified under 4 major groups-enhanced T cell activation (ITPKC, ORAI1, STIM1), dysregulated B cell signaling (CD40, BLK, FCGR2A), decreased apoptosis (CASP3), and altered transforming growth factor beta signaling (TGFB2, TGFBR2, MMP, SMAD). The review aims to highlight the role of several genetic risk factors that are linked with the increased susceptibility to KD.
Assuntos
Aneurisma Aórtico/genética , Vasos Coronários/patologia , Imunogenética/métodos , Síndrome de Linfonodos Mucocutâneos/genética , Animais , Aneurisma Aórtico/imunologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Síndrome de Linfonodos Mucocutâneos/imunologia , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Salmonella infection is most common in patients with infected aortic aneurysm, especially in Asia. When the aortic wall is heavily atherosclerotic, the intima is vulnerable to invasion by Salmonella, leading to the development of infected aortic aneurysm. By using THP-1 macrophage-derived foam cells to mimic atherosclerosis, we investigated the role of three Salmonella enterica serotypes - Typhimurium, Enteritidis, and Choleraesuis - in foam cell autophagy and inflammasome formation. Herein, we provide possible pathogenesis of Salmonella-associated infected aortic aneurysms. Three S. enterica serotypes with or without virulence plasmid were studied. Through Western blotting, we investigated cell autophagy induction and inflammasome formation in Salmonella-infected THP-1 macrophage-derived foam cells, detected CD36 expression after Salmonella infection through flow cytometry, and measured interleukin (IL)-1ß, IL-12, and interferon (IFN)-α levels through enzyme-linked immunosorbent assay. At 0.5 h after infection, plasmid-bearing S. Enteritidis OU7130 induced the highest foam cell autophagy - significantly higher than that induced by plasmid-less OU7067. However, plasmid-bearing S. Choleraesuis induced less foam cell autophagy than did its plasmid-less strain. In foam cells, plasmid-less Salmonella infection (particularly S. Choleraesuis OU7266 infection) led to higher CD36 expression than did plasmid-bearing strains infection. OU7130 and OU7266 infection induced the highest IL-1ß secretion. OU7067-infected foam cells secreted the highest IL-12p35 level. Plasmid-bearing S. Typhimurium OU5045 induced a higher IFN-α level than did other Salmonella serotypes. Salmonella serotypes are correlated with foam cell autophagy and IL-1ß secretion. Salmonella may affect the course of foam cells formation, or even aortic aneurysm, through autophagy.Salmonella infection is most common in patients with infected aortic aneurysm, especially in Asia. When the aortic wall is heavily atherosclerotic, the intima is vulnerable to invasion by Salmonella, leading to the development of infected aortic aneurysm. By using THP-1 macrophage-derived foam cells to mimic atherosclerosis, we investigated the role of three Salmonella enterica serotypes Typhimurium, Enteritidis, and Choleraesuis in foam cell autophagy and inflammasome formation. Herein, we provide possible pathogenesis of Salmonella-associated infected aortic aneurysms. Three S. enterica serotypes with or without virulence plasmid were studied. Through Western blotting, we investigated cell autophagy induction and inflammasome formation in Salmonella-infected THP-1 macrophage-derived foam cells, detected CD36 expression after Salmonella infection through flow cytometry, and measured interleukin (IL)-1ß, IL-12, and interferon (IFN)-α levels through enzyme-linked immunosorbent assay. At 0.5 h after infection, plasmid-bearing S. Enteritidis OU7130 induced the highest foam cell autophagy significantly higher than that induced by plasmid-less OU7067. However, plasmid-bearing S. Choleraesuis induced less foam cell autophagy than did its plasmid-less strain. In foam cells, plasmid-less Salmonella infection (particularly S. Choleraesuis OU7266 infection) led to higher CD36 expression than did plasmid-bearing strains infection. OU7130 and OU7266 infection induced the highest IL-1ß secretion. OU7067-infected foam cells secreted the highest IL-12p35 level. Plasmid-bearing S. Typhimurium OU5045 induced a higher IFN-α level than did other Salmonella serotypes. Salmonella serotypes are correlated with foam cell autophagy and IL-1ß secretion. Salmonella may affect the course of foam cells formation, or even aortic aneurysm, through autophagy.
Assuntos
Aneurisma Aórtico/microbiologia , Infecções por Salmonella/microbiologia , Salmonella typhimurium/patogenicidade , Animais , Aneurisma Aórtico/genética , Aneurisma Aórtico/imunologia , Linhagem Celular , Humanos , Interferon-alfa/genética , Interferon-alfa/imunologia , Interleucina-12/genética , Interleucina-12/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Antígeno Ki-1/genética , Antígeno Ki-1/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Monócitos/imunologia , Monócitos/microbiologia , Plasmídeos/genética , Plasmídeos/metabolismo , Infecções por Salmonella/genética , Infecções por Salmonella/imunologia , Salmonella typhimurium/genética , Salmonella typhimurium/fisiologia , Sorogrupo , VirulênciaRESUMO
The prevalence and extent of immunoglobulin G4 (IgG4)-positive cell infiltration were investigated in 282 surgical samples of aortic wall and aortic valve. Tissue infiltration of IgG4-positive cells was observed in 24 (17.3%) of 139 aortic valve samples and 46 (32%) of 143 aortic wall samples, and the condition of IgG4-positive cell infiltration > 30/hpf together with IgG4/CD138 ratio > 40% was observed in 2 (1.4%) of aortic valve samples and 14 (9.8%) of aortic wall samples. Among 275 patients, preoperative serum IgG4 level was available in 48 patients (50 samples), and it was > 135 mg/dL in only one patient. Of these 48 patients with serum IgG4 measurement, 29 patients had aortic valve stenosis and 12 had aortic aneurysm. Compared with 23 aortic stenosis patients without tissue infiltration of IgG4-positive cells in the aortic valve, six patients with IgG4-positive cell infiltration had a more prevalent smoking history (26% versus 83%) and borderline significantly higher serum IgG4 (median, 24.5 mg/dL versus 55.5 mg/dL), although either preoperative peak pressure gradient between left ventriculum and aorta or aortic valve area did not differ significantly between groups. Compared with six aortic aneurysm patients without tissue infiltration of IgG4-positive cells in the aortic wall, six patients with IgG4-positive cell infiltration had borderline significantly higher serum IgG4 (median, 28.9 mg/dL versus 68.2 mg/dL). The current study showed that tissue IgG4-positive infiltration is not a rare occurrence in the aortic stenosis and aortic aneurysm. Clinical significance of tissue IgG4-postive cell infiltration in these patients requires further investigation.
Assuntos
Aneurisma Aórtico/imunologia , Estenose da Valva Aórtica/imunologia , Doença Relacionada a Imunoglobulina G4/sangue , Imunoglobulina G/sangue , Plasmócitos/patologia , Idoso , Idoso de 80 Anos ou mais , Aorta/anatomia & histologia , Aorta/citologia , Aorta/diagnóstico por imagem , Aorta/cirurgia , Aneurisma Aórtico/sangue , Aneurisma Aórtico/patologia , Valva Aórtica/citologia , Valva Aórtica/diagnóstico por imagem , Valva Aórtica/cirurgia , Estenose da Valva Aórtica/sangue , Estenose da Valva Aórtica/patologia , Ecocardiografia/métodos , Feminino , Humanos , Doença Relacionada a Imunoglobulina G4/imunologia , Doença Relacionada a Imunoglobulina G4/patologia , Masculino , Pessoa de Meia-Idade , Plasmócitos/imunologia , Período Pré-Operatório , Estudos RetrospectivosRESUMO
Lentiviral vectors (LVs) transduce quiescent cells and provide stable integration to maintain transgene expression. Several approaches have been adopted to optimize LV safety profiles. Similarly, LV targeting has been tailored through strategies including the modification of envelope components, the use of specific regulatory elements, and the selection of appropriate administration routes. Models of aortic disease based on a single injection of pleiotropic LVs have been developed that efficiently transduce the three aorta layers in wild type mice. This approach allows the dissection of pathways involved in aortic aneurysm formation and the identification of targets for gene therapy in aortic diseases. LVs provide a fast, efficient, and affordable alternative to genetically modified mice to study disease mechanisms and develop therapeutic tools.
Assuntos
Proteína ADAMTS1/genética , Aneurisma Aórtico/terapia , Terapia Genética/métodos , Vetores Genéticos/química , Lentivirus/genética , Proteína ADAMTS1/antagonistas & inibidores , Proteína ADAMTS1/imunologia , Animais , Aneurisma Aórtico/genética , Aneurisma Aórtico/imunologia , Aneurisma Aórtico/patologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Regulação da Expressão Gênica , Vetores Genéticos/imunologia , Humanos , Imunidade Inata , Lentivirus/imunologia , Camundongos , Segurança do Paciente , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Transdução Genética/métodos , TransgenesRESUMO
BACKGROUND: The authors recently found that a CD31 agonist peptide reaches macrophages in injured aortas and exerts beneficial effects on apolipoprotein E-knockout (Apo E-/-) mice subjected to angiotensin (Ang) II infusion, a model of experimental acute aortic dissection and intramural hematoma (ADIM). OBJECTIVES: The purpose of this study was to evaluate the therapeutic potential of a drug-suitable agonist peptide in experimental ADIM. METHODS: P8RI, a retro-inverso sequence of the best candidate identified by functional in vitro screening of a peptide library, passed an absorption, distribution, metabolism, excretion and toxicology analysis. Apo E-/- mice (male, 28-week-old) implanted with Ang II-releasing pumps received P8RI (2.5 mg/kg/day) or vehicle from day 14 (n = 10/group). Leukocytes were analyzed by flow cytometry. Healing features of human and mouse dissected aortic segments were assessed by histology and immunofluorescence. The effect of CD31 on macrophages was evaluated using cells from CD31-/- mice and P8RI, in vitro. RESULTS: Human and experimental ADIM were characterized by the infiltration of proinflammatory macrophages. The absence of CD31 enhanced the proinflammatory polarization of macrophages, whereas the CD31 agonist P8RI favored reparative macrophages both in vitro and in vivo. The administration of P8RI after the occurrence of ADIM prevented aneurysmal transformation by promoting the resolution of intramural hematoma and the production of collagen in dissected aortas in vivo, associated with enrichment of M2 macrophages at the site of injury. CONCLUSIONS: CD31 signaling promotes the switching of proinflammatory macrophages to the reparative phenotype and favors the healing of experimental dissected aortas. Treatment with a drug-suitable CD31 agonist may facilitate the clinical management of ADIM.
Assuntos
Aneurisma Aórtico/imunologia , Dissecção Aórtica/imunologia , Macrófagos/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Angiotensina II , Animais , Masculino , Camundongos , Camundongos Knockout para ApoE , Molécula-1 de Adesão Celular Endotelial a Plaquetas/agonistasRESUMO
Acute medial dissection of aorta can occur in the context of a sudden and unexpected death. For medico-legal reasons it is important to estimate as accurately the histological age of dissections. We evaluated the additional value of a systematic application of immunohistochemistry, compared with conventional histology only, in determining chronological steps of injury and repair. Thirty two paraffin embedded specimens of aortic dissection were retrospectively allocated to one of four defined stages: acute (I), subacute (II), early organizing (III) and scarring (IV) using Hematoxylin and Eosin and Elastica van Gieson stained sections. Subsequent immunohistochemically staining was performed with the following markers: (myeloperoxidase (neutrophils), citrullinated-Histone 3 (neutrophil extracellular traps), CD68 (macrophages), CD3 (T-cells), CD31 and CD34 (endothelial cells), and smooth muscle actin. Immune stained sections were scored semi-quantitatively. Histologically, five cases were identified as stage I, 16 as II, 7 as III and 4 as IV. Additional immunostaining for smooth muscle cells and endothelial cells altered the classification in 25% of cases (all in groups II and III). Immunostaining and semi-quantitative grading of involvement of neutrophils, macrophages and NETs also provided specific distribution patterns over the 4 age categories, including unexpected involvement of the peri adventitial fat tissue. In conclusion, it appears that semi-quantitative immunohistochemistry of resident vascular wall cells, inflammatory cells and NETS represents a useful adjunct in detailed histopathological grading of the chronological age of aortic dissections.
Assuntos
Aorta/imunologia , Aneurisma Aórtico/imunologia , Dissecção Aórtica/imunologia , Imunofenotipagem/métodos , Túnica Média/imunologia , Remodelação Vascular , Tecido Adiposo/imunologia , Tecido Adiposo/patologia , Túnica Adventícia/imunologia , Túnica Adventícia/patologia , Dissecção Aórtica/patologia , Aorta/patologia , Aneurisma Aórtico/patologia , Biomarcadores/análise , Progressão da Doença , Armadilhas Extracelulares/imunologia , Feminino , Humanos , Imuno-Histoquímica , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/patologia , Fenótipo , Estudos Retrospectivos , Túnica Média/patologiaRESUMO
Diabetes is a negative risk factor for aortic aneurysm, but the underlying explanation for this phenomenon is unknown. We have previously demonstrated that cell division autoantigen 1 (CDA1), which enhances transforming growth factor-ß signaling, is upregulated in diabetes. We hypothesized that CDA1 plays a key role in conferring the protective effect of diabetes against aortic aneurysms. Male wild-type, CDA1 knockout (KO), apolipoprotein E (ApoE) KO, and CDA1/ApoE double-KO (dKO) mice were rendered diabetic. Whereas aneurysms were not observed in diabetic ApoE KO and wild-type mice, 40% of diabetic dKO mice developed aortic aneurysms. These aneurysms were associated with attenuated aortic transforming growth factor-ß signaling, reduced expression of various collagens, and increased aortic macrophage infiltration and matrix metalloproteinase 12 expression. In the well-characterized model of angiotensin II-induced aneurysm formation, concomitant diabetes reduced fatal aortic rupture and attenuated suprarenal aortic expansion, changes not seen in dKO mice. Furthermore, aortic CDA1 expression was downregulated â¼70% within biopsies from human abdominal aortic aneurysms. The identification that diabetes is associated with upregulation of vascular CDA1 and that CDA1 deletion in diabetic mice promotes aneurysm formation provides evidence that CDA1 plays a role in diabetes to reduce susceptibility to aneurysm formation.
Assuntos
Aneurisma da Aorta Abdominal/genética , Autoantígenos/genética , Diabetes Mellitus Experimental/metabolismo , Adulto , Idoso , Angiotensina II/farmacologia , Animais , Aneurisma Aórtico/induzido quimicamente , Aneurisma Aórtico/genética , Aneurisma Aórtico/imunologia , Aneurisma Aórtico/metabolismo , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/metabolismo , Ruptura Aórtica , Autoantígenos/metabolismo , Colágeno/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Macrófagos/imunologia , Masculino , Metaloproteinase 12 da Matriz/metabolismo , Camundongos , Camundongos Knockout , Camundongos Knockout para ApoE , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Transdução de Sinais , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Vasoconstritores/farmacologiaRESUMO
BACKGROUND: The diagnosis of Immunoglobulin G4 (IgG4)-related disease (IgG4-RD), in general, depends on serum IgG4 concentrations and histopathological findings; therefore, diagnosis of IgG4-RD in cardiovascular organs/tissues is often difficult owing to the risk of tissue sampling. METHODS: Prevalence of IgG4-positive lymphoplasmacytic infiltration in 103 consecutive cardiovascular surgical samples from 98 patients with various cardiovascular diseases was analyzed immunohistochemically. RESULTS: The diagnoses of the enrolled patients included aortic aneurysm (abdominal, n = 8; thoracic, n = 9); aortic dissection (n = 20); aortic stenosis (n = 24), aortic regurgitation (n = 10), and mitral stenosis/regurgitation (n = 17). In total, 10 (9.7%) of the 103 specimens showed IgG4-positive cell infiltration with various intensities; five of these were aortic valve specimens from aortic stenosis, and IgG4-positive cell infiltration was present at >10 /HPF in three of them. In one aortic wall sample from an abdominal aortic aneurysm, various histopathological features of IgG4-RD, such as IgG4-positive cell infiltration, obliterating phlebitis, and storiform fibrosis, were observed. CONCLUSIONS: IgG4-positive cell infiltration was observed in 9.7% of the surgical cardiovascular specimens, mainly in the aortic valve from aortic stenosis and in the aortic wall from aortic aneurysm. Whether IgG4-positive cell infiltration has pathophysiological importance in the development or progression of cardiovascular diseases should be investigated in future studies.
Assuntos
Doenças Cardiovasculares/imunologia , Quimiotaxia de Leucócito , Imunoglobulina G/análise , Plasmócitos/imunologia , Idoso , Idoso de 80 Anos ou mais , Aorta/imunologia , Aorta/patologia , Aneurisma Aórtico/imunologia , Aneurisma Aórtico/patologia , Valva Aórtica/imunologia , Valva Aórtica/patologia , Estenose da Valva Aórtica/imunologia , Estenose da Valva Aórtica/patologia , Aortografia/métodos , Biomarcadores/análise , Biópsia , Doenças Cardiovasculares/diagnóstico por imagem , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/cirurgia , Angiografia por Tomografia Computadorizada , Estudos Transversais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Plasmócitos/patologiaRESUMO
BACKGROUND: Acute aortic dissection (AD) is a lethal cardiovascular disease with severe inflammatory complications. Considering the proinflammatory properties of plasma mitochondrial DNA (mtDNA), we postulate that plasma mtDNA from activated platelets may be responsible for post-acute AD inflammatory responses. METHODS: We consecutively enrolled 68 patients with acute AD as well as matched hypertensive and healthy participants. Blood samples were collected on admission for blood routine tests, mtDNA assay, and inflammatory cytokine analysis. A computed tomography scan was used to evaluate the extent of dissections. RESULTS: Our results demonstrate that plasma mtDNA, platelet activation, and inflammatory levels were remarkably higher in acute AD patients than in hypertensive or healthy participants. These parameters were also higher in the Stanford A group than in the Stanford B group (p < 0.05). Bivariate correlation analysis demonstrated positive associations between mtDNA and inflammatory levels (tumor necrosis factor-α: r = 0.577; interleukin-6: r = 0.632), mtDNA and platelet activation (r = 0.642), and platelet activation and the extent of dissection (r = 0.635). CONCLUSION: Our study suggests that acute AD-induced tunica media exposure causes platelet activation, which leads to the initiation of inflammatory responses via the release of mtDNA into the circulation. Our study provides a novel fundamental basis and a potential therapeutic target for the prevention and treatment of post-AD inflammatory responses.
Assuntos
Aneurisma Aórtico/imunologia , Dissecção Aórtica/imunologia , DNA Mitocondrial/sangue , Ativação Plaquetária , Idoso , Dissecção Aórtica/sangue , Aneurisma Aórtico/sangue , Estudos de Casos e Controles , Citocinas/sangue , Humanos , Pessoa de Meia-IdadeRESUMO
The recent studies of molecular physiology of fibrillin and pathophysiology of inherent disorders of structure and function of connective tissue such as dissection and aneurysm of aorta, myxomatously altered cusps and prolapses of mitral valve, syndrome of hyper-mobility of joints, demonstrated that important role in development of these malformations play alterations of transfer of signals by growth factors and matrix cellular interaction. These conditions under manifesting Marfan's syndrome can be a consequence of anomalies of fibrillin-1 which deficiency unbrakes process of activation of transforming growth factor-ß (TGFß). The involvement of TGFß in pathogenesis of Marfan's syndrome permits consider antagonists of angiotensin-transforming enzymes as potential pharmaceuticals in therapy of this disease. The article presents analysis of publications' data related to this problem.
Assuntos
Aneurisma Aórtico/imunologia , Dissecção Aórtica/imunologia , Instabilidade Articular/imunologia , Síndrome de Marfan/imunologia , Prolapso da Valva Mitral/imunologia , Fator de Crescimento Transformador beta/imunologia , Dissecção Aórtica/tratamento farmacológico , Dissecção Aórtica/genética , Dissecção Aórtica/patologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Aneurisma Aórtico/tratamento farmacológico , Aneurisma Aórtico/genética , Aneurisma Aórtico/patologia , Tecido Conjuntivo/efeitos dos fármacos , Tecido Conjuntivo/imunologia , Tecido Conjuntivo/patologia , Fibrilina-1 , Fibrilinas , Regulação da Expressão Gênica , Humanos , Instabilidade Articular/tratamento farmacológico , Instabilidade Articular/genética , Instabilidade Articular/patologia , Síndrome de Marfan/tratamento farmacológico , Síndrome de Marfan/genética , Síndrome de Marfan/patologia , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/imunologia , Prolapso da Valva Mitral/tratamento farmacológico , Prolapso da Valva Mitral/genética , Prolapso da Valva Mitral/patologia , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Transdução de Sinais , Fator de Crescimento Transformador beta/genéticaRESUMO
BACKGROUND: Intestinal barrier dysfunction would lead to a rigorous inflammatory reaction due to the translocation of intestinal lumen-derived bacteria and endotoxins. The aim of the present study was to investigate whether intestinal barrier dysfunction occurs in patients with acute Stanford type A aortic dissection (ATAAD) and to determine its potential relationship with the plasma levels of several inflammatory biomarkers in the progression of ATAAD. DESIGN AND METHODS: Serum samples from a total of 46 patients with ATAAD and 36 healthy volunteers were prospectively collected and analyzed. The serum levels of diamine oxidase (DAO), lactate dehydrogenase (LDH), interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and C-reactive protein (CRP) were measured using colorimetric assay, enzyme-linked immunosorbent assay, and immunoturbidimetric assay. RESULTS: Serum levels of DAO, LDH, IL-6, TNF-α, and CRP in patients with ATAAD were significantly higher than those in healthy participants. A significantly positive correlation between DAO activity and IL-6 (r = .56, P < .001), TNF-α (r = .63, P < .001), and CRP (r = .53, P < .001) was observed. Moreover, the activity of DAO correlated negatively with the Pao 2/fraction of inspired oxygen (Fio 2) ratio (r = -.39, P = .007). CONCLUSIONS: Intestinal barrier dysfunction, reflected by an increased level of serum DAO, may play an important role in the development of systemic inflammatory responses in patients with ATAAD. Therefore, strategies of preserving a normal intestinal barrier function may open new horizons in the treatment of inflammation-related adverse events in the setting of ATAAD.
Assuntos
Aneurisma Aórtico/sangue , Dissecção Aórtica/sangue , Mediadores da Inflamação/sangue , Mucosa Intestinal/metabolismo , Síndrome de Resposta Inflamatória Sistêmica/sangue , Adulto , Idoso , Amina Oxidase (contendo Cobre)/sangue , Dissecção Aórtica/diagnóstico , Dissecção Aórtica/imunologia , Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/imunologia , Biomarcadores/sangue , Proteína C-Reativa/análise , Estudos de Casos e Controles , Feminino , Humanos , Interleucina-6/sangue , Mucosa Intestinal/imunologia , L-Lactato Desidrogenase/sangue , Masculino , Pessoa de Meia-Idade , Permeabilidade , Valor Preditivo dos Testes , Estudos Prospectivos , Síndrome de Resposta Inflamatória Sistêmica/diagnóstico , Síndrome de Resposta Inflamatória Sistêmica/imunologia , Fator de Necrose Tumoral alfa/sangueRESUMO
Immunoglobulin G4 (IgG4)-related disease is a systemic autoimmune disease that can affect various organs. Corticosteroid therapy is generally an effective treatment; however, IgG4-related aortic lesions pose a risk of aortic rupture related to corticosteroid use. Here, we report a case of IgG4-related periaortitis complicated with a false aneurysm during corticosteroid therapy. Although endovascular repair was successfully performed, autoimmune pancreatitis and sclerosing cholangitis emerged after surgery. The multiple lesions associated with IgG4-related disease were resolved through continuous corticosteroid therapy. Our case suggests that both appropriate surgical intervention and continuous corticosteroid therapy are essential for the treatment of IgG4-related periaortitis.
Assuntos
Corticosteroides/uso terapêutico , Falso Aneurisma/cirurgia , Aneurisma Aórtico/cirurgia , Doenças Autoimunes/tratamento farmacológico , Implante de Prótese Vascular , Procedimentos Endovasculares , Imunoglobulina G/imunologia , Fibrose Retroperitoneal/tratamento farmacológico , Idoso , Falso Aneurisma/diagnóstico , Falso Aneurisma/imunologia , Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/imunologia , Aortografia/métodos , Doenças Autoimunes/complicações , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/imunologia , Colangite Esclerosante/imunologia , Feminino , Humanos , Pancreatite/imunologia , Fibrose Retroperitoneal/complicações , Fibrose Retroperitoneal/diagnóstico , Fibrose Retroperitoneal/imunologia , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
Aortic aneurysms are common and life threatening problems with high rates of death. The initiation and progression of aneurysms are characterized by extensive extracellular matrix degradation and immune cells invasion within arterial wall. During the pathogenesis of all aneurysms, inflammation and immune cells play a significant role. Although T cells are abundant in aneurysm tissue, their functions in initiation and propagation of aneurysms remain unclear. This review summarizes the current state of knowledge of T lymphocytes on this disease and focuses on potential mechanisms of specific T cell responses.
Assuntos
Aneurisma Aórtico/imunologia , Linfócitos T/imunologia , Matriz Extracelular/imunologia , Humanos , Subpopulações de Linfócitos TRESUMO
The aim of this study was to provide data on the risk of developing chronic Q fever in patients with aorto-iliac disease and evidence of previous Q fever infection. Patients with an aortic and/or iliac aneurysm or aorto-iliac reconstruction (aorto-iliac disease) and evidence of previous Q fever infection were included. The presence of phase I and II Coxiella burnetii IgG antibodies was assessed periodically using immunofluorescence assay. A total of 111 patients with aorto-iliac disease were divided into three groups, based upon the serological profile [mean follow-up: 16 ± 9 months (mean ± standard deviation)]. Group 1 consisted of 30 patients with a serological trace of C. burnetii infection (negative IgG phase I, IgG phase II titer of 1:32). Of these, 36.7% converted to serological profile matching past resolved Q fever. Group 2 included 49 patients with negative IgG phase I titer and IgG phase II titer ≥1:64. No patients developed chronic Q fever, but 14.3% converted to a positive IgG phase I titer. Group 3 consisted of 32 patients with positive IgG phase I and positive IgG phase II titers, of which 9.4% developed chronic Q fever (significantly different from group 2, p = 0.039). The IgG phase I titer increased in 28.1% of patients (from 1:64 to 1:4,096). The risk of developing chronic Q fever in patients with aorto-iliac disease and previous Q fever infection with a positive IgG phase I titer was 9.4%. The IgG phase I titer increases or becomes positive in a substantial number of patients. A standardized serological follow-up is proposed.
Assuntos
Aneurisma Aórtico/imunologia , Coxiella burnetii/imunologia , Aneurisma Ilíaco/imunologia , Febre Q/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antibacterianos/sangue , Aneurisma Aórtico/sangue , Aneurisma Aórtico/microbiologia , Feminino , Humanos , Aneurisma Ilíaco/sangue , Aneurisma Ilíaco/microbiologia , Imunoglobulina G/sangue , Masculino , Febre Q/sangue , Febre Q/imunologia , Fatores de RiscoRESUMO
AIMS: To identify the frequency of immunoglobulin G4 (IgG4)-related aortitis in patients who undergo aorta surgery and are diagnosed by pathology as having chronic aortic inflammation and to compare IgG4-related aortitis with other non-infectious aortitises in terms of clinical characteristics. METHODS: The aorta specimen pathological reports of 1418 patients who underwent aortic aneurysm or dissection surgery were reviewed. In total, 41 had chronic aortic inflammation without atherosclerosis, cancer or infection. Their aorta biopsy specimens were subjected to IgG4 immunostaining. IgG4-related aortitis was diagnosed if the IgG4-positive plasma cell count exceeded 50 per high power field (HPF), the ratio of IgG4-positive to IgG-positive plasma cells exceeded 50% and dense lymphoplasmacytic infiltration, fibrosis and/or obliterative phlebitis were observed. RESULTS: Of the 41 non-infectious aortitis cases, 29, six and six had idiopathic aortitis, Takayasu's arteritis and Behcet's aortitis, respectively. Of the 29 idiopathic aortitis cases, three had IgG4-related aortitis. All were male and > 65 years of age. Two had thoracic aortic aneurysms and one had an abdominal aortic aneurysm. Their IgG4-positive plasma cell counts were 60/HPF or higher; lymphoplasmacytic infiltration and/or fibrosis, but not obliterative phlebitis, were observed. The IgG4-related aortitis cases were older (67 [range, 65-69] years) than the Takayasu's arteritis (47.5 [38-58] years) or Behcet's aortitis (47 [31-56] years) cases and more likely to be male than the Takayasu's arteritis cases (100% vs. 17%). CONCLUSION: In patients with chronic aortic inflammation, 7% had IgG4-related aortitis. This disease may be more common in older male patients than in other demographic groups.