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BACKGROUND: Trauma is the leading cause of death and disability for individuals under age 55. Many severely injured trauma patients experience complicated clinical courses despite appropriate initial therapy. We sought to identify novel circulating metabolomic signatures associated with clinical outcomes following trauma. STUDY DESIGN: Untargeted metabolomics and circulating plasma immune mediator analysis was performed on plasma collected during 3 post-injury time periods (<6 hours [h], 6 h-24h, day 2-day 5) in critically ill trauma patients enrolled between April 2004 and May 2013 at UPMC Presbyterian Hospital in Pittsburgh, PA. Inclusion criteria were age ≥ 18 years, blunt mechanism, ICU admission, and expected survival ≥ 24 h. Exclusion criteria were isolated head injury, spinal cord injury, and pregnancy. Exploratory endpoints included length of stay (overall and ICU), ventilator requirements, nosocomial infection, and Marshall organ dysfunction (MOD) score. The top 50 metabolites were isolated using repeated measures ANOVA and multivariate empirical Bayesian analysis for further study. RESULTS: Eighty-six patients were included for analysis. Sphingolipids were enriched significantly (chi-square, p < 10-6) among the top 50 metabolites. Clustering of sphingolipid patterns identified 3 patient subclasses: nonresponders (no time-dependent change in sphingolipids, n = 41), sphingosine/sphinganine-enhanced (n = 24), and glycosphingolipid-enhanced (n = 21). Compared with the sphingolipid-enhanced subclasses, nonresponders had longer mean length of stay, more ventilator days, higher MOD scores, and higher circulating levels of proinflammatory immune mediators IL-6, IL-8, IL-10, MCP1/CCL2, IP10/CXCL10, and MIG/CXCL9 (all p < 0.05), despite similar Injury Severity Scores (p = 0.12). CONCLUSIONS: Metabolomic analysis identified broad alterations in circulating plasma sphingolipids after blunt trauma. Circulating sphingolipid signatures and their association with both clinical outcomes and circulating inflammatory mediators suggest a possible link between sphingolipid metabolism and the immune response to trauma.
Assuntos
Metaboloma , Esfingolipídeos/sangue , Ferimentos não Penetrantes/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Cuidados Críticos/métodos , Cuidados Críticos/estatística & dados numéricos , Estado Terminal , Feminino , Humanos , Escala de Gravidade do Ferimento , Tempo de Internação/estatística & dados numéricos , Estudos Longitudinais , Masculino , Metabolômica , Pessoa de Meia-Idade , Escores de Disfunção Orgânica , Prognóstico , Estudos Prospectivos , Ferimentos não Penetrantes/diagnóstico , Ferimentos não Penetrantes/imunologia , Ferimentos não Penetrantes/terapia , Adulto JovemRESUMO
BACKGROUND AND AIMS: Liver ischemia/reperfusion injury (IRI) induces local and systemic inflammation in which neutrophil extracellular traps (NETs) are major drivers. IRI markedly augments metastatic growth, which is consistent with the notion that the liver IRI can serve as a premetastatic niche. Exercise training (ExT) confers a sustainable protection, reducing IRI in some animal models, and has been associated with improved survival in patients with cancer; however, the impact of ExT on liver IRI or development of hepatic metastases is unknown. APPROACH AND RESULTS: Mice were randomized into exercise (ExT) and sedentary groups before liver IRI and tumor injection. Computerized dynamic network analysis of 20 inflammatory mediators was used to dissect the sequence of mediator interactions after ischemia/reperfusion (I/R) that induce injury. ExT mice showed a significant decrease in hepatic IRI and tissue necrosis. This coincided with disassembly of complex networks among inflammatory mediators seen in sedentary mice. Neutrophil infiltration and NET formation were decreased in the ExT group, which suppressed the expression of liver endothelial cell adhesion molecules. Concurrently, ExT mice revealed a distinct population of infiltrating macrophages expressing M2 phenotypic genes. In a metastatic model, fewer metastases were present 3 weeks after I/R in the ExT mice, a finding that correlated with a marked increase in tumor-suppressing T cells within the tumor microenvironment. CONCLUSIONS: ExT preconditioning mitigates the inflammatory response to liver IRI, protecting the liver from injury and metastases. In light of these findings, potential may exist for the reduction of liver premetastatic niches induced by liver IRI through the use of ExT as a nonpharmacologic therapy before curative surgical approaches.
Assuntos
Armadilhas Extracelulares/imunologia , Inflamação , Hepatopatias , Metástase Neoplásica , Infiltração de Neutrófilos/imunologia , Condicionamento Físico Animal/métodos , Traumatismo por Reperfusão , Animais , Proliferação de Células , Modelos Animais de Doenças , Imunidade , Inflamação/etiologia , Inflamação/imunologia , Inflamação/terapia , Hepatopatias/imunologia , Hepatopatias/patologia , Hepatopatias/terapia , Camundongos , Metástase Neoplásica/imunologia , Metástase Neoplásica/terapia , Fatores de Proteção , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/patologia , Traumatismo por Reperfusão/terapia , Resultado do TratamentoRESUMO
BACKGROUND: Persons living with HIV (PLWH) are at risk of developing different phenotypes of chronic lung disease, including chronic obstructive pulmonary disease. Mechanisms underlying these phenotypes are unclear. OBJECTIVE: To identify clusters of peripheral inflammatory mediators associated with pulmonary function to determine inflammatory pathways and phenotypes of chronic obstructive pulmonary disease in PLWH and HIV-uninfected individuals. METHODS: Study participants were PLWH and HIV-uninfected individuals enrolled in the Pittsburgh HIV Lung Cohort. Pulmonary function tests were performed for all participants. Chest computed tomographic scans were performed in a subset of PLWH. Plasma levels of 19 inflammatory mediators were measured by Luminex or ELISA. Clusters were identified based on the expression pattern of inflammatory mediators in PLWH and HIV-uninfected individuals, and the relationships among clinical parameters were evaluated within clusters by using cluster and network analyses. RESULTS: In PLWH, we identified a distinct cluster with higher levels of Th1, Th2, and Th17 inflammatory mediators with increased complexity of these mediators and inferred presence of pathogenic Th17 cell types. Individuals in this cluster had worse airway obstruction and more radiographic emphysema. In HIV-uninfected individuals, a cluster with high-grade systemic inflammation also had worse diffusing capacity for carbon monoxide. CONCLUSIONS: Inflammatory pathways associated with pulmonary dysfunction in PLWH suggest multifaceted immune dysregulation involved in different phenotypes of pulmonary dysfunction with a potential specific contribution of the Th17 pathway to airway obstruction in PLWH. Identification of these associations may help in development of treatments that could alter the course of the disease.
Assuntos
Infecções por HIV/complicações , Infecções por HIV/fisiopatologia , Pneumopatias/complicações , Pneumopatias/fisiopatologia , Fenótipo , Adulto , Contagem de Linfócito CD4 , Monóxido de Carbono , Análise por Conglomerados , Estudos de Coortes , Feminino , Infecções por HIV/imunologia , Humanos , Pulmão/fisiopatologia , Pneumopatias/imunologia , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Enfisema Pulmonar , Testes de Função Respiratória , Fatores de Risco , Células Th1 , Células Th17 , Células Th2 , Estados UnidosRESUMO
The integrin family of cell adhesion molecules mediates homeostasis, signal transduction, and various other interactions between the cell and the extracellular matrix. Integrins are type-1 transmembrane glycoproteins located on the cell surface, widely expressed in leukocytes, which play an important role in the inflammatory pathway. The purpose of this review is to summarize the current state of anti-integrin therapy and to assess ongoing clinical trials in ocular disease. We performed a search on PubMed, CINAHL, and Embase for the published literature available using the MeSH terms: "integrin therapy" and "αLß2," "α4ß1" and "α4ß7," "αvß3," "αvß5," and "αvß1" and/or "ophthalmology," and "clinical trials." We used no language restrictions. We generated searches to account for synonyms of these keywords and MESH headings as follows: (1) "integrin," "therapy," or "treatment"; (2) "clinical trials," "ophthalmology," or "ocular." In addition, the analysis included phase 2 and phase 3 clinical trials with a minimal follow-up of six months. Integrin antagonists have shown their capacity to improve signs and symptoms of patients with dry eye disease, age-related macular degeneration, diabetic macular edema, and vitreomacular traction.
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Fatores Biológicos/uso terapêutico , Terapia Biológica/métodos , Oftalmopatias/terapia , Integrinas/antagonistas & inibidores , Oftalmopatias/metabolismo , HumanosRESUMO
AIM: To compare the effect of phacoemulsification on intraocular pressure (IOP) in patients with primary open angle glaucoma (POAG) and pseudoexfoliation glaucoma (PXG). METHODS: A retrospective comparative case series conducted at the Glaucoma Department at the Association to Prevent Blindness in Mexico. The study enrolled consecutive patients having phacoemulsification with intraocular lens (IOL) implantation and a diagnosis of POAG or PXG. Data about IOP values and number of glaucoma medications used was collected at baseline, 1, 3, 6 and 12mo postoperatively. RESULTS: The study enrolled 88 patients (88 eyes). After phacoemulsification, there was a statistically significant reduction in IOP values and glaucoma medications use compared to baseline in both POAG and PXG patients (P<0.001). In the POAG group, a 20% decrease in IOP values was evidenced, and a 56.5% reduction in the number of medications used at the one-year follow-up. The PXG group showed a 20.39%, and a 34.46% decrease in IOP and number of medications used, respectively. A significant difference in the mean ΔIOP (postoperative changes in IOP) was evidenced between groups (P=0.005). The reduction of the postsurgical IOP mean values in both groups, the POAG group showed a greater reduction in IOP values compared to the PXG group. CONCLUSION: In both types of glaucoma, phacoemulsification cataract surgery can result in a significant IOP reduction (20%) over a 12mo follow-up period. The number of medications used is also significantly reduced up to 12mo after surgery, especially in the PXG group.
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Bcl-3 is an atypical member of the inhibitor of NF-kappa B family of proteins since it can function as a coactivator of transcription. Although this oncogene was described in leukemia, it is overexpressed in a number of solid tumors as well. The oncogenic potential of Bcl-3 has been associated with its capacity to increase proliferation by means of activating the cyclin D1 promoter and to its antiapoptotic role mediated by the inhibiton of p53 activity. In the course of dissecting these properties, we found that depleting Bcl-3 protein using shRNAs induce a decrease of proliferation and clonogenic survival associated with the induction of multinucleation and increased ploidy. These effects were associated with a DNA damage response, a delay in G2/M checkpoint and the induction of centrosome amplification.
Assuntos
Aneuploidia , Centrossomo , Neoplasias/genética , Proteínas Proto-Oncogênicas/genética , Fatores de Transcrição/genética , Proteína 3 do Linfoma de Células B , Ciclo Celular , Ciclina D1/genética , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Neoplasias/patologia , Regiões Promotoras GenéticasRESUMO
El factor de crecimiento transformante beta-1 (TGF-alfa1) es una citoquina con diversas funciones en procesos inflamatorios y el sistema inmune. Un método comercial comúnmente usado para la determinación de TGF-alfa1 es el ensayo de inmunoadsorción enzimática (ELISA), que detecta directamente la forma activa, o la forma inactiva (latente), después de activarla por acidificación o por tratamiento con urea. Este método constituye la mejor opción debido a su simplicidad, especificidad y sensibilidad, sin embargo, existen algunas discrepancias en la literatura científica relacionadas con los factores que activan el TGF-alfa1 latente in vitro e in vivo. Por este motivo decidimos comparar los efectos del calor y de la acidificación en la activación del complejo inactivo. Los resultados muestran que aunque ambos tratamientos activan el TGF-alfa1 latente, la activación térmica es más eficiente que la acidificación. Estos resultados sugieren que los datos publicados reportando valores absolutos de TGF-alfa1, basados sólo en ELISA, se deben interpretar cautelosamente. Asimismo, para la detección de TGF-alfa1 por este método es recomendable usar como control positivo tanto la activación térmica, como la acidificación.
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Humanos , Linfócitos B , Cooperação Linfocítica , Ensaio de Imunoadsorção Enzimática , Imunoadsorventes , Sistema Imunitário/crescimento & desenvolvimentoRESUMO
Ukrain is a reaction product of different alkaloids from Chelidonium majus L. (celandine) conjugated with thiophosphoric acid. It has immunoregulatory effects on T lymphocyte subsets and cytotoxic and cytostatic effects on various malignant cells. Although Ukrain has been reported to induce alterations in the cell cycle and tubulin polymerization, the specific cellular target has not been described. Since antineoplasic agents induce NF-kappaB and their effects are regulated by this transcription factor, we investigated its possible participation in the apoptotic effects of Ukrain. Ukrain induced apoptosis in a panel of cancer cell lines by activating the intrinsic cell death pathway, as demonstrated by the cleavage of caspase 9 and the upregulation and cleavage of caspase 3. The effect was reversible, since long exposures (24 hours or more) were needed, as verified by clonogenic assays. Gene reporter assays showed that Ukrain activated NF-kappa B. Nevertheless, this activation was not required for, and did not modulate, the Ukrain effect: neither blockage of activation by a dominant negative version of Ikappa-B alpha or a Bcl-3 siRNA, nor activation of the pathway by overexpression of IKK2, changed the response to the drug. In conclusion, Ukrain induced apoptosis in HeLa cervical cancer cells by activating the intrinsic pathway. In contrast to other antineoplasic drugs, the effects of Ukrain were not regulated by NF-kappa B.