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1.
PLoS One ; 15(8): e0238006, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32857814

RESUMO

This study aimed to evaluate the effects of two prebiotics in different concentrations on nutrient digestibility, fermentative products and immunological variables in adult dogs. Twenty-four adult dogs were randomly divided into six blocks according to their metabolic body weights (BW0.75); within these groups, dogs were randomized to four treatments: control without prebiotics (CO); inclusion of 0.5% prebiotic blend Yes-Golf (B1); inclusion of 1.0% galactooligosaccharide (GOS); and inclusion of 1.0% prebiotic blend Yes-Golf (B2). The experiment lasted 30 days, with 20 days adaptation and 10 days stool and blood collection. Results were analyzed for normality and means were separated by ANOVA and adjusted by the Tukey test at the significance level of 5.0%. Prebiotic supplementation had no effect on apparent digestibility coefficients (ADC), total stool production and fecal scores (p > 0.05). Prebiotics evaluated also did not alter fecal pH, nor the concentrations of ammonia, lactic acid, short chain fatty acids (SCFA) and most fecal branched chain fatty acids (BCFA) (p > 0.05). The addition of GOS decreased the concentration of iso-valeric acid (p = 0.0423). Regarding immunological variables, concentrations of fecal IgA were not influenced by the treatments. Treatments GOS and B2 increased the total number of polymorphonuclear cells, as well as the oxidative burst in relation to treatments B1 and CO (p < 0.0001). Treatment B2 improved the rate of S. aureus phagocytosis in relation to CO (p = 0.0111), and both the GOS and B2 treatments had a better index for E. coli phagocytosis than the CO treatment (p = 0.0067). In conclusion, there was indication that both prebiotics GOS and B2 at 1.0% inclusion improved the immunity of healthy dogs.


Assuntos
Colo/efeitos dos fármacos , Oligossacarídeos/farmacologia , Prebióticos , Animais , Colo/imunologia , Colo/microbiologia , Dieta/veterinária , Cães , Ácidos Graxos Voláteis/análise , Fezes/química , Microbioma Gastrointestinal/efeitos dos fármacos , Concentração de Íons de Hidrogênio , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Fagocitose/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Staphylococcus aureus/fisiologia
2.
Clin Appl Thromb Hemost ; 26: 1076029620943293, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32735131

RESUMO

Since the onset of the global pandemic in early 2020, coronavirus disease 2019 (COVID-19) has posed a multitude of challenges to health care systems worldwide. In order to combat these challenges and devise appropriate therapeutic strategies, it becomes of paramount importance to elucidate the pathophysiology of this illness. Coronavirus disease 2019, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), is characterized by a dysregulated immune system and hypercoagulability. COVID-associated coagulopathy (CAC) was recognized based on profound d-dimer elevations and evidence of microthrombi and macrothrombi, both in venous and arterial systems. The underlying mechanisms associated with CAC have been suggested, but not clearly defined. The model of immunothrombosis illustrates the elaborate crosstalk between the innate immune system and coagulation. The rendering of a procoagulant state in COVID-19 involves the interplay of many innate immune pathways. The SARS-CoV2 virus can directly infect immune and endothelial cells, leading to endothelial injury and dysregulation of the immune system. Activated leukocytes potentiate a procoagulant state via release of intravascular tissue factor, platelet activation, NETosis, and inhibition of anticoagulant mechanisms. Additional pathways of specific relevance in CAC include cytokine release and complement activation. All these mechanisms have recently been reported in COVID-19. Immunothrombosis provides a comprehensive perspective of the several synergistic pathways pertinent to the pathogenesis of CAC.


Assuntos
Betacoronavirus , Transtornos da Coagulação Sanguínea/virologia , Infecções por Coronavirus/complicações , Pneumonia Viral/complicações , Transtornos da Coagulação Sanguínea/etiologia , Transtornos da Coagulação Sanguínea/patologia , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Células Endoteliais/patologia , Células Endoteliais/virologia , Humanos , Imunidade Inata , Leucócitos/metabolismo , Leucócitos/patologia , Pandemias , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Trombofilia/imunologia , Trombofilia/virologia , Trombose/etiologia , Trombose/imunologia , Trombose/virologia
3.
PLoS One ; 15(7): e0234150, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32614830

RESUMO

To investigate a Florida manatee (Trichechus manatus latirostris) mortality event following a red tide bloom in Southwest Florida, an RNA sequencing experiment was conducted. Gene expression changes in white blood cells were assessed in manatees rescued from a red tide affected area (n = 4) and a control group (n = 7) using RNA sequencing. The genes with the largest fold changes were compared between the two groups to identify molecular pathways related to cellular and disease processes. In total, 591 genes (false discovery rate <0.05) were differentially expressed in the red tide group. Of these, 158 were upregulated and 433 were downregulated. This suggests major changes in white blood cell composition following an exposure to red tide. The most highly upregulated gene, Osteoclast associated 2C immunoglobulin-like receptor (OSCAR), was upregulated 12-fold. This gene is involved in initiating the immune response and maintaining a role in adaptive and innate immunity. The most highly downregulated gene, Piccolo presynaptic cytomatrix protein (PCLO), was downregulated by a factor of 977-fold. This gene is associated with cognitive functioning and neurotransmitter release. Downregulation of this gene in other studies was associated with neuronal loss and neuron synapse dysfunction. Among the cellular pathways that were most affected, immune response, including inflammation, wounds and injuries, cell proliferation, and apoptosis were the most predominant. The pathway with the most differentially expressed genes was the immune response pathway with 98 genes involved, many of them downregulated. Assessing the changes in gene expression associated with red tide exposure enhances our understanding of manatee immune response to the red tide toxins and will aid in the development of red tide biomarkers.


Assuntos
Perfilação da Expressão Gênica , Proliferação Nociva de Algas , Trichechus manatus/fisiologia , Animais , Buffy Coat/citologia , Florida , Ontologia Genética , Sistema Imunitário , Leucócitos/metabolismo , Toxinas Marinhas/envenenamento , Redes e Vias Metabólicas/genética , Neurotoxinas/envenenamento , Oxocinas/envenenamento , Envenenamento/sangue , Envenenamento/reabilitação , Envenenamento/veterinária , RNA Mensageiro/biossíntese , RNA Mensageiro/sangue , Transcriptoma , Trichechus manatus/sangue , Trichechus manatus/genética , Trichechus manatus/imunologia
4.
Arterioscler Thromb Vasc Biol ; 40(9): 2279-2292, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32611241

RESUMO

OBJECTIVE: Recruitment of neutrophils and formation of neutrophil extracellular traps (NETs) contribute to lethality in acute mesenteric infarction. To study the impact of the gut microbiota in acute mesenteric infarction, we used gnotobiotic mouse models to investigate whether gut commensals prime the reactivity of neutrophils towards formation of neutrophil extracellular traps (NETosis). Approach and Results: We applied a mesenteric ischemia-reperfusion (I/R) injury model to germ-free (GF) and colonized C57BL/6J mice. By intravital imaging, we quantified leukocyte adherence and NET formation in I/R-injured mesenteric venules. Colonization with gut microbiota or monocolonization with Escherichia coli augmented the adhesion of leukocytes, which was dependent on the TLR4 (Toll-like receptor-4)/TRIF (TIR-domain-containing adapter-inducing interferon-ß) pathway. Although neutrophil accumulation was decreased in I/R-injured venules of GF mice, NETosis following I/R injury was significantly enhanced compared with conventionally raised mice or mice colonized with the minimal microbial consortium altered Schaedler flora. Also ex vivo, neutrophils from GF and antibiotic-treated mice showed increased LPS (lipopolysaccharide)-induced NETosis. Enhanced TLR4 signaling in GF neutrophils was due to elevated TLR4 expression and augmented IRF3 (interferon regulatory factor-3) phosphorylation. Likewise, neutrophils from antibiotic-treated conventionally raised mice had increased NET formation before and after ischemia. Increased NETosis in I/R injury was abolished in conventionally raised mice deficient in the TLR adaptor TRIF. In support of the desensitizing influence of enteric LPS, treatment of GF mice with LPS via drinking water diminished LPS-induced NETosis in vitro and in the mesenteric I/R injury model. CONCLUSIONS: Collectively, our results identified that the gut microbiota suppresses NETing neutrophil hyperreactivity in mesenteric I/R injury, while ensuring immunovigilance by enhancing neutrophil recruitment.


Assuntos
Armadilhas Extracelulares/metabolismo , Microbioma Gastrointestinal , Isquemia Mesentérica/metabolismo , Mesentério/irrigação sanguínea , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Traumatismo por Reperfusão/metabolismo , Vênulas/metabolismo , Animais , Bacillus subtilis/patogenicidade , Adesão Celular , Células Cultivadas , Modelos Animais de Doenças , Escherichia coli/patogenicidade , Armadilhas Extracelulares/microbiologia , Feminino , Vida Livre de Germes , Interações Hospedeiro-Patógeno , Migração e Rolagem de Leucócitos , Leucócitos/metabolismo , Leucócitos/microbiologia , Masculino , Isquemia Mesentérica/microbiologia , Isquemia Mesentérica/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Traumatismo por Reperfusão/microbiologia , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Vênulas/microbiologia , Vênulas/patologia
5.
PLoS One ; 15(7): e0235486, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32609762

RESUMO

Thioredoxin-interacting protein (TXNIP) inhibits the activity of thioredoxin (TXN), leading to increased oxidative stress. Expression of the TXNIP gene is regulated by DNA methylation. However, no study has reported the influence of lifestyle factors on TXNIP DNA methylation. Our goal was to determine the association between smoking habits and TXNIP DNA methylation levels in a Japanese population. We conducted a cross-sectional study of 417 subjects (180 males and 237 females) participating in a health examination. We used a pyrosequencing assay to determine TXNIP DNA methylation levels in leukocytes. The mean TXNIP DNA methylation level in current smokers (75.3%) was significantly lower than that in never and ex-smokers (never: 78.1%, p < 0.001; ex: 76.9%, p = 0.013). Multivariable logistic regression analyses showed that the OR for TXNIP DNA hypomethylation was significantly higher in current smokers than that in never smokers, and significantly higher in current smokers with years of smoking ≥ 35 and Brinkman Index ≥ 600 compared to that in non-smokers. In conclusion, we found that current smokers had TXNIP DNA hypomethylation compared to never and ex-smokers. Moreover, long-term smoking and high smoking exposure also were associated with TXNIP DNA hypomethylation.


Assuntos
Proteínas de Transporte/genética , Metilação de DNA , Hábitos , Leucócitos/metabolismo , Fumar/genética , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade
6.
Ecotoxicol Environ Saf ; 200: 110761, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32470682

RESUMO

Benzo()pyrene [B()P], widely originated from environmental pollution or food process such as roasting and frying, is a strong mutagen and potent carcinogen. Utilization of hawthorn has been reported against physical mutagens. Our study found that hawthorn extract (HE) contained abundant phenolic compounds, wherein chlorogenic acid was 2.78 mg/g, procyanidine B2 was 3.58 mg/g, epicatechin was 2.99 mg/g DW, which may contribute to anti-genotoxicity activity. So, the role of HE against B()P-induced genotoxicity in C57BL/6 mice was further assessed. Fifty mice were distributed into five groups: control group, B()P group (30 mg/kg, i.p.), B()P + HE-L group (100 mg/kg, i.g.), B()P + HE-M group (200 mg/kg, i.g.), B()P + HE-H group (400 mg/kg, i.g.). Mice were orally administered with solutions of HE for 10 days and injected intraperitoneally with B()P for 3 days from the 8th day. Results showed that B()P can induce significantly pathological damage in liver, lung and spleen, as well as decrease white blood cells (WBCs). Remarkably elevated levels of reactive oxygen species (ROS), DNA strand breaks (DSBs) and G1 cell cycle arrest were also found in B()P group, with upregulated expressions of p-H2AX, p-p53 and p21 in bone marrow cells. With administration of HE, liver, lung and spleen injury significantly mitigated, while WBCs were evidently increased in B()P-treated mice. Consistently, HE markedly reduced level of ROS, DSBs and G1 cell cycle arrest accompanied by reducing expressions of p-H2AX, p-p53 and p21 in bone marrow cells. Combined, these results indicated a protective role of HE on B()P-induced genotoxicity.


Assuntos
Benzo(a)pireno/toxicidade , Crataegus/química , Dano ao DNA/efeitos dos fármacos , Mutagênicos/toxicidade , Extratos Vegetais/farmacologia , Substâncias Protetoras/farmacologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/metabolismo , Expressão Gênica/efeitos dos fármacos , Histonas/genética , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Fígado/efeitos dos fármacos , Fígado/patologia , Pulmão/efeitos dos fármacos , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/isolamento & purificação , Substâncias Protetoras/isolamento & purificação , Espécies Reativas de Oxigênio/metabolismo , Baço/efeitos dos fármacos , Baço/patologia , Proteína Supressora de Tumor p53/genética
7.
Arterioscler Thromb Vasc Biol ; 40(7): 1635-1650, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32434410

RESUMO

OBJECTIVE: Thrombocytopenia is associated with many viral infections suggesting virions interact with and affect platelets. Consistently, viral particles are seen inside platelets, and platelet activation markers are detected in viremic patients. In this article, we sought mechanistic insights into these virion/platelet interactions by examining how platelets endocytose, traffic, and are activated by a model virion. Approach and Results: Using fluorescently tagged HIV-1 pseudovirions, 3-dimensional structured illumination microscopy, and transgenic mouse models, we probed the interactions between platelets and virions. Mouse platelets used known endocytic machinery, that is, dynamin, VAMP (vesicle-associated membrane protein)-3, and Arf6 (ADP-ribosylation factor 6), to take up and traffic HIV-1 pseudovirions. Endocytosed HIV-1 pseudovirions trafficked through early (Rab4+) and late endosomes (Rab7+), and then to an LC3+ (microtubule-associated protein 1A/1B-light chain 3) compartment. Incubation with virions induced IRAK4 (interleukin 1 receptor-associated kinase 4), Akt (protein kinase B), and IKK (IκB kinase) activation, granule secretion, and platelet-leukocyte aggregate formation. This activation required TLRs (Toll-like receptors) and MyD88 (myeloid differentiation primary response protein 88) but was less extensive and slower than activation with thrombin. In vivo, HIV-1 pseudovirions injection led to virion uptake and platelet activation, as measured by IKK activation, platelet-leukocyte aggregate formation, and mild thrombocytopenia. All were decreased in VAMP-3-/- and, megakaryocyte/platelet-specific, Arf6-/- mice. Similar platelet activation profiles (increased platelet-leukocyte aggregates, plasma platelet factor 4, and phospho-IκBα) were detected in newly diagnosed and antiretroviral therapy-controlled HIV-1+ patients. CONCLUSIONS: Collectively, our data provide mechanistic insights into the cell biology of how platelets endocytose and process virions. We propose a mechanism by which platelets sample the circulation and respond to potential pathogens that they take up.


Assuntos
Plaquetas/metabolismo , Endocitose , Infecções por HIV/sangue , HIV-1/patogenicidade , Ativação Plaquetária , Trombocitopenia/sangue , Receptores Toll-Like/sangue , Vírion , Fatores de Ribosilação do ADP/sangue , Fatores de Ribosilação do ADP/genética , Animais , Antirretrovirais/uso terapêutico , Plaquetas/virologia , Agregação Celular , Células Cultivadas , Infecções por HIV/diagnóstico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Humanos , Quinase I-kappa B/sangue , Quinase I-kappa B/genética , Leucócitos/metabolismo , Leucócitos/virologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/sangue , Fator 88 de Diferenciação Mieloide/genética , Fator Plaquetário 4/sangue , Fator Plaquetário 4/genética , Trombocitopenia/diagnóstico , Trombocitopenia/virologia , Receptores Toll-Like/deficiência , Receptores Toll-Like/genética , Proteína 3 Associada à Membrana da Vesícula/sangue , Proteína 3 Associada à Membrana da Vesícula/genética
8.
Am J Physiol Heart Circ Physiol ; 319(1): H51-H65, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32412791

RESUMO

Although there is a strong association between cigarette smoking exposure (CSE) and vascular endothelial dysfunction (VED), the underlying mechanisms by which CSE triggers VED remain unclear. Therefore, studies were performed to define these mechanisms using a chronic mouse model of cigarette smoking (CS)-induced cardiovascular disease mirroring that in humans. C57BL/6 male mice were subjected to CSE for up to 48 wk. CSE impaired acetylcholine (ACh)-induced relaxation of aortic and mesenteric segments and triggered hypertension, with mean arterial blood pressure at 32 and 48 wk of exposure of 122 ± 6 and 135 ± 5 mmHg compared with 99 ± 4 and 102 ± 6 mmHg, respectively, in air-exposed mice. CSE led to monocyte activation with superoxide generation in blood exiting the pulmonary circulation. Macrophage infiltration with concomitant increase in NADPH oxidase subunits p22phox and gp91phox was seen in aortas of CS-exposed mice at 16 wk, with further increase out to 48 wk. Associated with this, increased superoxide production was detected that decreased with Nox inhibition. Tetrahydrobiopterin was progressively depleted in CS-exposed mice but not in air-exposed controls, resulting in endothelial nitric oxide synthase (eNOS) uncoupling and secondary superoxide generation. CSE led to a time-dependent decrease in eNOS and Akt expression and phosphorylation. Overall, CSE induces vascular monocyte infiltration with increased NADPH oxidase-mediated reactive oxygen species generation and depletes the eNOS cofactor tetrahydrobiopterin, uncoupling eNOS and triggering a vicious cycle of oxidative stress with VED and hypertension. Our study provides important insights toward understanding the process by which smoking contributes to the genesis of cardiovascular disease and identifies biomarkers predictive of disease.NEW & NOTEWORTHY In a chronic model of smoking-induced cardiovascular disease, we define underlying mechanisms of smoking-induced vascular endothelial dysfunction (VED). Smoking exposure triggered VED and hypertension and led to vascular macrophage infiltration with concomitant increase in superoxide and NADPH oxidase levels as early as 16 wk of exposure. This oxidative stress was accompanied by tetrahydrobiopterin depletion, resulting in endothelial nitric oxide synthase uncoupling with further superoxide generation triggering a vicious cycle of oxidative stress and VED.


Assuntos
Endotélio Vascular/metabolismo , Leucócitos/metabolismo , Estresse Oxidativo , Lesão por Inalação de Fumaça/metabolismo , Poluição por Fumaça de Tabaco/efeitos adversos , Vasodilatação , Animais , Aorta/metabolismo , Aorta/fisiopatologia , Pressão Sanguínea , Endotélio Vascular/fisiopatologia , Masculino , Artérias Mesentéricas/metabolismo , Artérias Mesentéricas/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Lesão por Inalação de Fumaça/etiologia , Lesão por Inalação de Fumaça/fisiopatologia , Superóxidos/metabolismo
9.
PLoS One ; 15(4): e0231834, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298370

RESUMO

Markers for monitoring clearance of Mycobacterium tuberculosis (Mtb) infection during anti-TB drug treatment could facilitate management of tuberculosis (TB) treatment, but are lacking. We aimed to screen for Mtb clearance markers from in-vitro-infected leucocytes and to evaluate these markers in followed-up active TB (ATB) patients and latent TB (LTBI) cases after anti-TB drug treatment. Extracellular proteins from primary leucocytes infected with each of the Mtb lineages (East-Asian, Indo-Oceanic, Euro-American and the laboratory strain H37Rv) were screened as possible clearance markers. Leucocytes infected with Staphylococcus aureus acted as controls. The proteomic analysis was performed using GeLC-MS/MS. Several quantitative and qualitative candidate clearance markers were found. These proteins were suppressed during the infection stage of all Mtb lineages and re-expressed after bacillary clearance. PSTK, FKBP8 and MGMT were common clearance markers among the four Mtb lineages in our model. Only PSTK was a potential clearance marker based on western blot validation analysis from culture supernatants. The PSTK marker was further validated with western blot analysis using serum samples (n = 6) from ATB patients and LTBI cases during anti-TB drug treatment, and from healthy controls (n = 3). Time-dependent increase of PSTK was found both in ATB and LTBI patients during the course of anti-TB drug treatment, but not in healthy controls. We have demonstrated that PSTK is a potential treatment-monitoring marker for active and latent TB.


Assuntos
Tuberculose Latente/sangue , Leucócitos/metabolismo , Mycobacterium tuberculosis , Fosforilase Quinase/metabolismo , Proteoma/metabolismo , Tuberculose/sangue , Adulto , Biomarcadores/sangue , Cromatografia Líquida , Metilases de Modificação do DNA/sangue , Enzimas Reparadoras do DNA/sangue , Feminino , Humanos , Tuberculose Latente/tratamento farmacológico , Leucócitos/microbiologia , Masculino , Pessoa de Meia-Idade , Proteoma/efeitos dos fármacos , Proteômica , Proteínas de Ligação a Tacrolimo/sangue , Espectrometria de Massas em Tandem , Fatores de Tempo , Tuberculose/tratamento farmacológico , Proteínas Supressoras de Tumor/sangue , Adulto Jovem
10.
PLoS One ; 15(4): e0230053, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32298279

RESUMO

Although anxiety disorders are among the most prevalent of psychiatric disorders, childhood trauma-related studies seldom consider anxiety proneness as distinct aetiological contributor. We aimed to distinguish between trauma- and anxiety-associated physiological profiles. South African adolescent volunteers were categorised for trauma exposure (CTQ, mean score 39±11) and anxiety proneness (AP)(CASI, mean score 37±7, STAI-T, mean score 41±8). Circulating hormone and leukocyte glucocorticoid receptor levels, as well as leukocyte functional capacity, were assessed. AP was associated with lower DHEAs (P<0.05) and higher leukocyte GR expression (P<0.05). DHEAs was also negatively correlated with anxiety sensitivity (CASI, P<0.05). In conclusion, AP may have more predictive power than trauma in terms of health profile. Increased glucocorticoid sensitivity previously reported after trauma, may be a unique function of anxiety and not trauma exposure per se. DHEAs concentration was identified as potentially useful marker for monitoring progressive changes in HPA-axis sensitivity and correlated with psychological measures of anxiety.


Assuntos
Transtornos de Ansiedade/sangue , Desidroepiandrosterona/sangue , Regulação da Expressão Gênica , Leucócitos/metabolismo , Receptores de Glucocorticoides/sangue , Estresse Psicológico/sangue , Adolescente , Transtornos de Ansiedade/psicologia , Feminino , Humanos , Masculino , África do Sul , Estresse Psicológico/psicologia
11.
Am J Physiol Lung Cell Mol Physiol ; 318(6): L1172-L1182, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32130031

RESUMO

Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease and is associated with chronic pulmonary inflammation caused by cigarette smoking, with contributions from immune cells such as neutrophils, macrophages, and lymphocytes. Although matrix metalloproteinases are well known to contribute to emphysema progression, the role of a disintegrin and metalloproteinase (ADAM) family proteins, other major metalloproteinases, in disease pathogenesis is largely unknown. ADAM17 is a major sheddase that cleaves various cell surface proteins, including CD62L, an adhesion molecule that plays a critical role in promoting the migration of immune cells to the site of inflammation. In the present study, we aimed to investigate the potential role of ADAM17 and CD62L in the development of elastase-induced emphysema. Control and Adam17flox/flox/Mx1-Cre (Adam17ΔMx1) mice (8-10 wk old) were intratracheally injected with 5 units of porcine pancreas elastase and monitored for 35 days after injection. Lung alveolar destruction was evaluated by analyzing the mean linear intercepts of lung tissue specimens and by histopathological examination. Mean linear intercepts data indicated that the degree of elastase-induced emphysema was significantly more severe in Adam17ΔMx1 mice. Furthermore, flow cytometry showed that CD62L+ neutrophil, CD62L+ macrophage, and CD62L+ B lymphocyte numbers were significantly increased in Adam17ΔMx1 mice. Moreover, the pharmacological depletion of CD62L+ cells with a CD62L-neutralizing antibody ameliorated the extent of emphysema in Adam17ΔMx1 mice. Collectively, these results suggest that ADAM17 possibly suppresses the progression of emphysema by proteolytically processing CD62L in immune cells and that ADAM17 and CD62L could be novel therapeutic targets for treating pulmonary emphysema.


Assuntos
Proteína ADAM17/metabolismo , Selectina L/metabolismo , Leucócitos/metabolismo , Enfisema Pulmonar/induzido quimicamente , Enfisema Pulmonar/imunologia , Animais , Antioxidantes/metabolismo , Apoptose , Líquido da Lavagem Broncoalveolar , Contagem de Células , Quimiocinas/metabolismo , Células Epiteliais/metabolismo , Regulação da Expressão Gênica , Pulmão/patologia , Macrófagos/patologia , Metaloproteinase 12 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Testes de Neutralização , Oxidantes/metabolismo , Elastase Pancreática , Enfisema Pulmonar/genética , Enfisema Pulmonar/patologia
12.
Biol Pharm Bull ; 43(3): 474-479, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32115505

RESUMO

Creatine transporter (CRT) deficiency (CRT-D) results in a significant reduction of brain creatine levels, which causes various neurological symptoms in early childhood, and diagnosis of the severity of CRT-D based on the residual CRT transport activity in liquid biopsy samples would be beneficial for early intervention. The apparent reduction in creatine transport activity in CRT-D is thought to be due to reduced intrinsic CRT-mediated creatine transport per CRT protein and/or reduced absolute CRT protein expression on the plasma membranes. The purpose of this study was thus to determine the normal level of intrinsic CRT-mediated creatine transport activity based on absolute CRT protein quantification using rat CRT-overexpressing HEK293 cells (CRT/HEK293 cells), and to clarify creatine transport in erythrocyte- and leukocyte-enriched fractions isolated from the circulating blood of rats. The intrinsic creatine transport rate was calculated to be 0.237 µL/(min·fmol CRT) based on the initial uptake rate and the absolute CRT protein level in CRT/HEK293 cells. Taking into account Avogadro's constant, the creatine transport activity per CRT protein is estimated to be 1190 creatine/(min·CRT molecule) in the presence of [14C]creatine at an extracellular concentration of 5 µM. Isolated leukocyte-enriched fraction exhibited mRNA expression of CRT and partially Na+-dependent [14C]creatine transport, whereas erythrocytes showed neither. These characteristics suggest that the leukocytes contain the CRT-mediated creatine uptake system, and are available for evaluation of residual CRT transport activity in CRT-D patients.


Assuntos
Creatina/metabolismo , Leucócitos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Animais , Transporte Biológico , Membrana Celular/metabolismo , Eritrócitos/metabolismo , Células HEK293 , Humanos , Masculino , Transportadores de Ácidos Monocarboxílicos , Proteínas do Tecido Nervoso , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores , Ratos
13.
Am J Physiol Renal Physiol ; 318(4): F982-F993, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150444

RESUMO

Studies examining mechanisms of Dahl salt-sensitive (SS) hypertension have implicated the infiltration of leukocytes in the kidneys, which contribute to renal disease and elevated blood pressure. However, the signaling pathways by which leukocytes traffic to the kidneys remain poorly understood. The present study nominated a signaling pathway by analyzing a kidney RNA sequencing data set from SS rats fed either a low-salt (0.4% NaCl) diet or a high-salt (4.0% NaCl) diet. From this analysis, chemokine (C-C motif) ligand 2 (CCL2) and chemokine (C-C motif) receptor 2 (CCR2) were nominated as a potential pathway modifying renal leukocyte infiltration and contributing to SS hypertension. The functional role of the CCL2/CCR2 pathway was tested by daily administration of CCR2 antagonist (RS-102895 at 5 mg·kg-1·day-1 in DMSO) or DMSO vehicle for 3 or 21 days by intraperitoneal injections during the high salt challenge. Blood pressure, renal leukocyte infiltration, and renal damage were evaluated. The results demonstrated that RS-102895 treatment ameliorated renal damage (urinary albumin excretion; 43.4 ± 5.1 vs. 114.7 ± 15.2 mg/day in vehicle, P < 0.001) and hypertension (144.3 ± 2.2 vs. 158.9 ± 4.8 mmHg in vehicle, P < 0.001) after 21 days of high-salt diet. It was determined that renal leukocyte infiltration was blunted by day 3 of the high-salt diet (1.4 ± 0.1 vs. 1.9 ± 0.2 in vehicle × 106 CD45+ cells/kidney, P = 0.034). An in vitro chemotaxis assay validated the effect of RS-102895 on leukocyte chemotaxis toward CCL2. The results suggest that increased CCL2 in SS kidneys is important in the early recruitment of leukocytes, and blockade of this recruitment by administering RS-102895 subsequently blunted the renal damage and hypertension.


Assuntos
Quimiocina CCL2/metabolismo , Quimiotaxia de Leucócito , Hipertensão/metabolismo , Rim/metabolismo , Leucócitos/metabolismo , Cloreto de Sódio na Dieta , Animais , Anti-Hipertensivos/farmacologia , Pressão Arterial , Benzoxazinas/farmacologia , Células Cultivadas , Quimiocina CCL2/antagonistas & inibidores , Quimiocina CCL2/genética , Quimiotaxia de Leucócito/efeitos dos fármacos , Modelos Animais de Doenças , Hipertensão/patologia , Hipertensão/fisiopatologia , Hipertensão/prevenção & controle , Rim/efeitos dos fármacos , Rim/patologia , Leucócitos/efeitos dos fármacos , Leucócitos/patologia , Masculino , Piperidinas/farmacologia , Ratos Endogâmicos Dahl , Receptores CCR2/antagonistas & inibidores , Receptores CCR2/metabolismo , Transdução de Sinais , Regulação para Cima
14.
J Cancer Res Clin Oncol ; 146(5): 1115-1124, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32144534

RESUMO

PURPOSE: Aberrant DNA methylation could regulate the expression of tumor suppressor gene DLEC1 and oncogene PBX3 and was related to the occurrence and prognosis of gastric cancer (GC). In this study, the associations between DLEC1 and PBX3 promoter methylation in peripheral blood leukocytes (PBLs) and the risk and prognosis of GC were investigated. METHODS: The methylation status of DLEC1 and PBX3 promoter in PBLs of 368 GC cases and 382 controls was detected by the methylation-sensitive high-resolution melting (MS-HRM) method. Logistic and Cox regression were adopted to analyze the associations of DLEC1 and PBX3 methylation with GC risk and prognosis, respectively. Confounding biases were controlled by propensity score (PS). RESULTS: Compared with negative methylation (Nm), DLEC1-positive methylation (Pm) was associated with increased GC risk in PS (OR 2.083, 95% CI 1.220-3.558, P = 0.007), but PBX3 Pm was not associated with GC risk. In the elderly group (≥ 60 years), DLEC1 Pm was associated with increased GC risk (OR 2.951, 95% CI 1.426-6.104, P = 0.004). The combined effects between DLEC1 methylation and consumption of dairy products, fried food intake and Helicobacter pylori (H. pylori) infection on GC risk were discovered (ORc 3.461, 95% CI 1.847-6.486, P < 0.001, ORc 3.246, 95% CI 1.708-6.170, P < 0.001 and ORc 2.964, 95% CI 1.690-5.197, P < 0.001, respectively). Furthermore, DLEC1 and PBX3 methylation were not associated with GC prognosis. CONCLUSION: DLEC1 methylation in PBLs and the combined effects of gene-environment can influence GC risk.


Assuntos
Proteínas de Homeodomínio/genética , Leucócitos/metabolismo , Proteínas Proto-Oncogênicas/genética , Neoplasias Gástricas/genética , Proteínas Supressoras de Tumor/genética , Estudos de Casos e Controles , Metilação de DNA , DNA de Neoplasias/sangue , DNA de Neoplasias/genética , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Infecções por Helicobacter/genética , Helicobacter pylori/isolamento & purificação , Humanos , Leucócitos/patologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Neoplasias Gástricas/sangue , Neoplasias Gástricas/patologia
15.
Gene ; 741: 144579, 2020 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-32171822

RESUMO

Interleukin (IL)-10 is a critical anti-inflammatory and late cytokine being produced after the proinflammatory mediators while IL-6 is a promptly synthesized cytokine in response to inflammation in mammals. This chronological expression of interleukin (Il)-6 and Il-10 was also found in grass carp head kidney leucocytes (HKLs) treated by heat-killed Aeromonas hydrophila, supporting the possible interplay between grass carp (gc)Il-6 and gcIl-10 in HKLs. Our further findings were in agreement with this hypothesis that recombinant gcIl-6 (rgcIl-6) promptly and transiently increased gcil10 mRNA levels in grass carp HKLs. Moreover, rgcIl-6 enhanced its own mRNA level and this self-enhancement of gcil6 mRNA level could be partially blocked by rgcIl-10. These results collectively suggest that gcIl-10 production stimulated by gcIl-6 may provide a negative feedback to gcIl-6 production. Interestingly, rgcIl-6 significantly decreased gcil10 mRNA levels in grass carp HKLs after the treatment for 12 and 24 h in contrast to its enhancement of gcil10 levels after the treatment for 3 h. Involvement of Stat3 but not MEK, p38 MAPK or JNK pathway in the increase of gcil10 mRNA levels by rgcIl-6 was revealed by using the signaling pathway inhibitors. This was supported by the fact that rgcIl-6 stimulated Stat3 phosphorylation in grass carp HKLs. Furthermore, rgcIl-6 had no effect on the stability of gcil10 mRNA after the treatment for 3 to 36 h while it increased gcil10 promoter activity after the treatment for 24 h. Taken these data together, gcIl-6 can stimulate Il-10 production at early stage but subsequently inhibit il10 mRNA expression in grass carp HKLs, shedding light on the dynamic regulation of il10 mRNA expression by Il-6 in fish immune cells.


Assuntos
Carpas/genética , Interleucina-10/genética , Interleucina-6/genética , Fator de Transcrição STAT3/genética , Sequência de Aminoácidos , Animais , Regulação da Expressão Gênica/genética , Rim Cefálico/metabolismo , Leucócitos/metabolismo
16.
Adv Ther ; 37(3): 1145-1155, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32002809

RESUMO

INTRODUCTION: Immune checkpoint inhibitors have provided substantial benefit in non-small cell lung cancer (NSCLC) with unprecedented results in terms of survival. However, the identification of reliable predictive biomarkers to these agents is lacking and multiple clinicopathological factors have been evaluated. The aim of this study was to analyze the potential role of neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and lactate dehydrogenase (LDH) levels in patients with pretreated NSCLC receiving nivolumab. METHODS: This was a retrospective multicenter study involving 14 Italian centers, evaluating the role of some laboratory results in patients with NSCLC treated with nivolumab in the second or later lines of therapy for at least four doses and with a disease re-staging. RESULTS: A total of 187 patients with available pretreatment laboratory results were included. NLR levels below 5 were associated with an improvement in terms of both progression-free survival (PFS) (p = 0.028) and overall survival (OS) (p = 0.001), but not in terms of overall response rate (ORR) or disease control rate (DCR). Moreover, PLR levels below 200 were associated with longer PFS (p = 0.0267) and OS (p = 0.05), as well as higher ORR (p = 0.04) and DCR (p = 0.001). In contrast, LDH levels above the upper normal limit (UNL) were not associated with significant impact on patient outcomes. CONCLUSIONS: Patients with pretreated NSCLC and high pretreatment levels of NLR and PLR may experience inferior outcomes with nivolumab. Therefore, in this subgroup of patients with poor prognosis the use of alternative therapeutic strategies may be a valuable option, especially in programmed cell death ligand 1 (PD-L1)-negative patients and/or in the presence of other additional poor prognostic factors.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Leucócitos/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neutrófilos/metabolismo , Nivolumabe/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/sangue , Feminino , Humanos , Contagem de Leucócitos , Neoplasias Pulmonares/sangue , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos
17.
Cardiovasc Diabetol ; 19(1): 22, 2020 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-32075646

RESUMO

BACKGROUND: Little is known about whether mitochondria 8-hydroxy-2'-deoxyguanosine (8-OHdG), a biomarker of mitochondrial DNA (mtDNA) oxidative damage, contributes to the development of coronary artery disease (CAD) in diabetic patients. Here, we explored the associations of mtDNA 8-OHdG in leukocytes with obstructive CAD, coronary stenosis severity, cardiovascular biomarkers, and 1-year adverse outcomes after coronary revascularization in patients with type 2 diabetes mellitus (T2DM). METHODS: In a total of 1920 consecutive patients with T2DM who underwent coronary angiography due to symptoms of angina or angina equivalents, the presence of obstructive CAD, the number of diseased vessels with ≥ 50% stenosis, and modified Gensini score were cross-sectionally evaluated; the level of mtDNA 8-OHdG was quantified by quantitative PCR. Then, 701 of 1920 diabetic patients who further received coronary revascularization completed 1-year prospective follow-up to document major adverse cardiovascular and cerebral events (MACCEs). In vitro experiments were also performed to observe the effects of mtDNA oxidative damage in high glucose-cultured human umbilical vein endothelial cells (HUVECs). RESULTS: Cross-sectionally, greater mtDNA 8-OHdG was associated with increased odds of obstructive CAD (odds ratio [OR] 1.38, 95% CI confidence interval 1.24-1.52), higher degree of coronary stenosis (number of diseased vessels: OR 1.29, 95% CI 1.19-1.41; modified Gensini scores: OR 1.28, 95% CI 1.18-1.39), and higher levels of C-reactive protein (ß 0.18, 95% CI 0.06-0.31) after adjusting for confounders. Sensitivity analyses using propensity score matching yielded similar results. Stratification by smoking status showed that the association between mtDNA 8-OHdG and obstructive CAD was most evident in current smokers (Pinteration < 0.01). Prospectively, the adjusted hazards ratio per 1-SD increase in mtDNA 8-OHdG was 1.59 (95% CI 1.33-1.90) for predicting 1-year MACCEs after revascularization. In HUVECs, exposure to antimycin A, an inducer for mtDNA oxidative damage, led to adverse alterations in markers of mitochondrial and endothelia function. CONCLUSION: Greater mtDNA 8-OHdG in leukocytes may serve as an independent risk factor for CAD in patients with T2DM.


Assuntos
8-Hidroxi-2'-Desoxiguanosina/sangue , Doença da Artéria Coronariana/sangue , Estenose Coronária/sangue , Dano ao DNA , DNA Mitocondrial/sangue , Diabetes Mellitus Tipo 2/sangue , Leucócitos/metabolismo , Idoso , Biomarcadores/sangue , Células Cultivadas , China/epidemiologia , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/terapia , Estenose Coronária/diagnóstico por imagem , Estenose Coronária/epidemiologia , Estenose Coronária/terapia , Estudos Transversais , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Revascularização Miocárdica/efeitos adversos , Estresse Oxidativo , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
18.
EBioMedicine ; 52: 102647, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32028068

RESUMO

BACKGROUND: Immunotherapy, including checkpoint inhibition, has remarkably improved prognosis in advanced melanoma. Despite this success, acquired resistance is still a major challenge. The T cell costimulatory receptor TNFRSF9 (also known as 4-1BB and CD137) is a promising new target for immunotherapy and two agonistic antibodies are currently tested in clinical trials. However, little is known about epigenetic regulation of the encoding gene. In this study we investigate a possible correlation of TNFRSF9 DNA methylation with gene expression, clinicopathological parameters, molecular and immune correlates, and response to anti-PD-1 immunotherapy to assess the validity of TNFRSF9 methylation to serve as a biomarker. METHODS: We performed a correlation analyses of methylation at twelve CpG sites within TNFRSF9 with regard to transcriptional activity, immune cell infiltration, mutation status, and survival in a cohort of N = 470 melanoma patients obtained from The Cancer Genome Atlas. Furthermore, we used quantitative methylation-specific PCR to confirm correlations in a cohort of N = 115 melanoma patients' samples (UHB validation cohort). Finally, we tested the ability of TNFRSF9 methylation and expression to predict progression-free survival (PFS) and response to anti-PD-1 immunotherapy in a cohort comprised of N = 121 patients (mRNA transcription), (mRNA ICB cohort) and a case-control study including N = 48 patients (DNA methylation, UHB ICB cohort). FINDINGS: We found a significant inverse correlation between TNFRSF9 DNA methylation and mRNA expression levels at six of twelve analyzed CpG sites (P ≤ 0.005), predominately located in the promoter flank region. Consistent with its role as costimulatory receptor in immune cells, TNFRSF9 mRNA expression and hypomethylation positively correlated with immune cell infiltrates and an interferon-γ signature. Furthermore, elevated TNFRSF9 mRNA expression and TNFRSF9 hypomethylation correlated with superior overall survival. In patients receiving anti-PD-1 immunotherapy (mRNA ICB cohort), we found that TNFRSF9 hypermethylation and reduced mRNA expression correlated with poor PFS and response. INTERPRETATION: Our study suggests that TNFRSF9 mRNA expression is regulated via DNA methylation. The observed correlations between TNFRSF9 DNA methylation or mRNA expression with known features of response to immune checkpoint blockage suggest TNFRSF9 methylation could serve as a biomarker in the context of immunotherapies. Concordantly, we identified a correlation between TNFRSF9 DNA methylation and mRNA expression with disease progression in patients under immunotherapy. Our study provides rationale for further investigating TNFRSF9 DNA methylation as a predictive biomarker for response to immunotherapy. FUNDING: AF was partly funded by the Mildred Scheel Foundation. SF received funding from the University Hospital Bonn BONFOR program (O-105.0069). DN was funded in part by DFG Cluster of Excellence ImmunoSensation (EXC 1023). The funders had no role in study design, data collection and analysis, interpretation, decision to publish, or preparation of the manuscript; or any aspect pertinent to the study.


Assuntos
Metilação de DNA , Epigênese Genética , Regulação Neoplásica da Expressão Gênica , Melanoma/etiologia , Melanoma/patologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Biomarcadores Tumorais , Estudos de Casos e Controles , Citocinas/metabolismo , Humanos , Interferon gama , Leucócitos/imunologia , Leucócitos/metabolismo , Leucócitos/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Melanoma/mortalidade , Melanoma/terapia , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , RNA Mensageiro
19.
J Nanobiotechnology ; 18(1): 31, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066449

RESUMO

BACKGROUND: Myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are two of the major players involved in the inhibition of anti-tumor immune response in cancer patients, leading to poor prognosis. Selective targeting of myeloid cells has therefore become an attractive therapeutic strategy to relieve immunosuppression and, in this frame, we previously demonstrated that lipid nanocapsules (LNCs) loaded with lauroyl-modified gemcitabine efficiently target monocytic MDSCs in melanoma patients. In this study, we investigated the impact of the physico-chemical characteristics of LNCs, namely size and surface potential, towards immunosuppressive cell targeting. We exploited myeloid cells isolated from glioblastoma patients, which play a relevant role in the immunosuppression, to demonstrate that tailored nanosystems can target not only tumor cells but also tumor-promoting cells, thus constituting an efficient system that could be used to inhibit their function. RESULTS: The incorporation of different LNC formulations with a size of 100 nm, carrying overall positive, neutral or negative charge, was evaluated on leukocytes and tumor-infiltrating cells freshly isolated from glioblastoma patients. We observed that the maximum LNC uptake was obtained in monocytes with neutral 100 nm LNCs, while positively charged 100 nm LNCs were more effective on macrophages and tumor cells, maintaining at low level the incorporation by T cells. The mechanism of uptake was elucidated, demonstrating that LNCs are incorporated mainly by caveolae-mediated endocytosis. CONCLUSIONS: We demonstrated that LNCs can be directed towards immunosuppressive cells by simply modulating their size and charge thus providing a novel approach to exploit nanosystems for anticancer treatment in the frame of immunotherapy.


Assuntos
Antimetabólitos Antineoplásicos/química , Desoxicitidina/análogos & derivados , Glioblastoma/tratamento farmacológico , Imunossupressores/química , Lipídeos/química , Macrófagos/metabolismo , Células Supressoras Mieloides/metabolismo , Nanocápsulas/química , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Desoxicitidina/química , Desoxicitidina/farmacologia , Composição de Medicamentos , Endocitose , Humanos , Imunossupressores/farmacologia , Imunoterapia/métodos , Leucócitos/metabolismo , Tamanho da Partícula , Transdução de Sinais , Propriedades de Superfície
20.
PLoS One ; 15(2): e0228954, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32027731

RESUMO

Aortic dissection may induce a systemic inflammatory reaction. The etiological backgrounds for elevation of the white blood cell count remain to be clarified. In 466 patients with acute type A aortic dissection treated surgically within 48 hours of symptom onset, the etiologic background of an elevated admission white blood cell count and the effect of such elevation on outcomes were assessed retrospectively. Patients' white blood cell count differed significantly in relation to the extent of dissection, with a median (25th, 75th percentile) white blood cell count of 10.4 (8.1, 13.9) x 103/µL for dissection confined to the ascending aorta, 10.5 (8.2,13.) 103/µL for dissection extending to the aortic arch/descending aorta, 11.1 (8.2, 13.7) x 103/µL for extension to the abdominal aorta, and 13.3 (9.8, 15.9) x 103/µL for extension to the iliac artery (p<0.001). With 11.0 x 103/µL used as the cut-off value for white blood cell count elevation, multivariable analysis showed current smoking (p<0.001; odds ratio, 2.79), dissection extending to the iliac artery (p = 0.006; odds ratio, 1.79), age (p = 0.007, odds ratio, 0.98), and no coronary ischemia (p = 0.027, odds ratio, 2.22) to be factors related to the elevated white blood cell count. Mean age differed significantly between patients with and without an elevated white blood cell count (62.3 vs. 68.3 years, p <0.001). Although in-hospital mortality was similar (7.5% vs.10.9%, p = 0.19), 5-year survival was lower in patients without an elevated count (85.7% vs. 78.6%, p = 0.019), reflecting their more advanced age. In conclusion, our data suggest that dissection morphology and patient age influence the acute phase systemic inflammatory response associated with an elevated white blood cell count in patients with ATAAD. A better understanding of this relation may help optimize diagnosis and perioperative care.


Assuntos
Aneurisma Dissecante/metabolismo , Aorta/cirurgia , Leucocitose/etiologia , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Aneurisma Dissecante/sangue , Aneurisma Dissecante/cirurgia , Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/sangue , Aneurisma da Aorta Torácica/cirurgia , Feminino , Mortalidade Hospitalar , Humanos , Contagem de Leucócitos/métodos , Leucócitos/metabolismo , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos , Fatores de Risco
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