RESUMEN
OBJECTIVES: Longitudinal tau quantification may provide a useful marker of drug efficacy in clinical trials. Different tau PET tracers may have different sensitivity to longitudinal changes, but without a head-to-head dataset or a carefully designed case-matching procedure, comparing results in different cohorts can be biased. In this study, we compared the tau PET tracers, 18F-MK6240 and 18F-flortaucipir (FTP), both cross-sectionally and longitudinally by case-matching subjects in the AIBL and ADNI longitudinal cohort studies. METHODS: A subset of 113 participants from AIBL and 113 from ADNI imaged using 18F-MK6240 and 18F-FTP respectively, with baseline and follow-up, were matched based on baseline clinical diagnosis, MMSE, age and amyloid (Aß) PET centiloid value. Subjects were grouped as 64 Aß- cognitively unimpaired (CU), 22 Aß+ CU, 14 Aß+ mild cognitive impairment (MCI) and 13 Aß+ Alzheimer's disease (AD). Tracer retention was measured in the mesial, temporoparietal, rest of the cortex, and a meta-temporal region composed of entorhinal, inferior/middle temporal, fusiform, parahippocampus and amygdala. T-tests were employed to assess group separation at baseline using SUVR Z-scores and longitudinally using SUVR%/Yr. RESULTS: Both tracers detected statistically significant differences at baseline in most regions between all clinical groups. Only 18F-MK6240 showed statistically significant higher rate of SUVR increase in Aß+ CU compared to Aß- CU in the mesial, meta-temporal and temporoparietal regions. CONCLUSION: 18F-MK6240 appears to be a more sensitive tracer for change in tau level at the preclinical stage of AD.
Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Péptidos beta-Amiloides/metabolismo , Proteínas tau/metabolismo , Estudios Longitudinales , Estudios Transversales , Tomografía de Emisión de Positrones/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismoRESUMEN
Influenza A virus (IAV) infections are a common cause of acute exacerbations of chronic obstructive pulmonary disease (AECOPD). Oxidative stress is increased in COPD, IAV-induced lung inflammation and AECOPD. Therefore, we investigated whether targeting oxidative stress with the Nox2 oxidase inhibitors and ROS scavengers, apocynin and ebselen could ameliorate lung inflammation in a mouse model of AECOPD. Male BALB/c mice were exposed to cigarette smoke (CS) generated from 9 cigarettes per day for 4 days. On day 5, mice were infected with 1 × 10(4.5) PFUs of the IAV Mem71 (H3N1). BALF inflammation, viral titers, superoxide production and whole lung cytokine, chemokine and protease mRNA expression were assessed 3 and 7 days post infection. IAV infection resulted in a greater increase in BALF inflammation in mice that had been exposed to CS compared to non-smoking mice. This increase in BALF inflammation in CS-exposed mice caused by IAV infection was associated with elevated gene expression of pro-inflammatory cytokines, chemokines and proteases, compared to CS alone mice. Apocynin and ebselen significantly reduced the exacerbated BALF inflammation and pro-inflammatory cytokine, chemokine and protease expression caused by IAV infection in CS mice. Targeting oxidative stress using apocynin and ebselen reduces IAV-induced lung inflammation in CS-exposed mice and may be therapeutically exploited to alleviate AECOPD.
Asunto(s)
Acetofenonas/administración & dosificación , Azoles/administración & dosificación , Compuestos de Organoselenio/administración & dosificación , Neumonía/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Humanos , Virus de la Influenza A/efectos de los fármacos , Virus de la Influenza A/patogenicidad , Isoindoles , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Neumonía/patología , Neumonía/virología , Enfermedad Pulmonar Obstructiva Crónica/patología , Enfermedad Pulmonar Obstructiva Crónica/virología , Humo/efectos adversos , Fumar/efectos adversos , Nicotiana/efectos adversosRESUMEN
Clinical studies have indicated increased gelatinase activity in the airways of patients suffering from chronic obstructive pulmonary disease caused by tobacco smoke. The present study aimed to determine whether acute exposure to tobacco smoke per se causes a substantial and lasting impact on gelatinases and their inhibitors in the peripheral airways of atopic and nonatopic human subjects. Bronchoscopy with bronchoalveolar lavage (BAL) was performed on occasional smokers with and without atopy before and after smoking 10 cigarettes over a 48-h period. Samples from a group of never-smokers not exposed to tobacco smoke served as controls. Gelatinase identity and activity were measured using zymography, and gelatinase activity assay and concentrations of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of MMP (TIMP)-1 and TIMP-2 were measured using ELISA. The results revealed no pronounced changes in identity, net activity or concentration of the gelatinases or changes in concentrations of TIMP-1 and TIMP-2 in BAL fluid before and after acute exposure to tobacco smoke. In conclusion, the present experimental study indicates that acute exposure to tobacco smoke does not cause any substantial impact on gelatinases or their inhibitors in the peripheral airways, irrespective of atopy status, a finding that is compatible with the fact that it takes many years of tobacco smoking to establish chronic obstructive pulmonary disease.
Asunto(s)
Líquido del Lavado Bronquioalveolar/química , Fumar/efectos adversos , Adulto , Femenino , Gelatinasas/efectos de los fármacos , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/efectos de los fármacos , Metaloproteinasa 9 de la Matriz/efectos de los fármacos , Inhibidor Tisular de Metaloproteinasa-1/efectos de los fármacos , Inhibidor Tisular de Metaloproteinasa-2/efectos de los fármacosRESUMEN
Peritoneal dialysis (PD) is a well established method of depuration in uremic patients. Standard dialysis solutions currently in use are not biocompatible with the peritoneal membrane. Studying effects of dialysate on peritoneal membrane in humans is still a challenge. There is no consensus on the ideal experimental model so far. We, therefore, wanted to develop a new experimental non-uremic rabbit model of peritoneal dialysis, which would be practical, easy to conduct, not too costly, and convenient to investigate the long-term effect of dialysis fluids. The study was done on 17 healthy Chinchilla male and female rabbits, anesthetized with Thiopental in a dose of 0.5 mg/kg body mass. A catheter, specially made from Tro-soluset (Troge Medical GMBH, Hamburg, Germany) infusion system, was then surgically inserted and tunneled from animals' abdomen to their neck. The planned experimental procedure was 4 weeks of peritoneal dialysate instillation. The presented non-uremic rabbit model of peritoneal dialysis is relatively inexpensive, does not require sophisticated technology and was well tolerated by the animals. Complications such as peritonitis, dialysis fluid leakage, constipation and catheter obstruction were negligible. This model is reproducible and can be used to analyze the effects of different dialysis solutions on the rabbit peritoneal membrane.
Asunto(s)
Soluciones para Diálisis/efectos adversos , Modelos Animales de Enfermedad , Diálisis Peritoneal/métodos , Peritoneo/efectos de los fármacos , Uremia/terapia , Animales , Materiales Biocompatibles/administración & dosificación , Materiales Biocompatibles/farmacología , Catéteres de Permanencia , Femenino , Masculino , Enfermedades Peritoneales/inducido químicamente , Enfermedades Peritoneales/prevención & control , Peritoneo/ultraestructura , Conejos , Resultado del TratamientoRESUMEN
Chronic obstructive pulmonary disease (COPD) is a major incurable global health burden and will become the third largest cause of death in the world by 2020. It is currently believed that an exaggerated inflammatory response to inhaled irritants, in particular cigarette smoke, causes progressive airflow limitation. This inflammation, where macrophages and neutrophils are prominent, leads to oxidative stress, emphysema (loss of lung structure), small airways fibrosis and mucus hypersecretion. However, COPD responds poorly to current anti-inflammatory treatments including potent glucocorticosteroids, which produce little or no benefit. In this review we consider the therapeutic potential of targeting granulocyte macrophage-colony stimulating factor (GM-CSF) for the treatment of COPD. GM-CSF is a major regulator of both macrophage and neutrophil activation and survival in the lung-these cells are intimately linked to COPD. Animal data indicates that neutralisation of GM-CSF ameliorates experimental COPD and predicts therapeutic utility in treating stable COPD and treating exacerbations. As such, GM-CSF represents an attractive therapeutic target for the treatment of COPD.
Asunto(s)
Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Animales , Humanos , Pulmón/inmunología , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Neumonía/prevención & control , Enfermedad Pulmonar Obstructiva Crónica/inmunologíaRESUMEN
Chronic obstructive pulmonary disease (COPD) is characterised by persistent airflow limitation, neutrophilic inflammation, macrophage accumulation, and the production of cytokines, chemokines and proteases. Cigarette smoking is the major cause of COPD and there is currently no satisfactory therapy to help treat individuals with this disease. A better understanding of the cellular and molecular responses triggered by cigarette smoke may provide new molecular targets for the development of therapeutic agents. This brief review highlights some of the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure.
Asunto(s)
Modelos Animales de Enfermedad , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Animales , Humanos , Enfermedad Pulmonar Obstructiva Crónica/etiología , Fumar/efectos adversos , Fumar/fisiopatologíaRESUMEN
Cigarette smoke exposure is a major determinant of adverse lung health, but the molecular processes underlying its effects on inflammation and immunity remain poorly understood. Therefore, we sought to understand whether inflammatory and host defense determinants are affected during subchronic cigarette smoke exposure. Dose-response and time course studies of lungs from Balb/c mice exposed to smoke generated from 3, 6, and 9 cigarettes/day for 4 days showed macrophage- and S100A8-positive neutrophil-rich inflammation in lung tissue and bronchoalveolar lavage (BAL) fluid, matrix metalloproteinase (MMP) and serine protease induction, sustained NF-kappaB translocation and binding, and mucus cell induction but very small numbers of CD3+CD4+ and CD3+CD8+ lymphocytes. Cigarette smoke had no effect on phospho-Akt but caused a small upregulation of phospho-Erk1/2. Activator protein-1 and phospho-p38 MAPK could not be detected. Quantitative real-time PCR showed upregulation of chemokines (macrophage inflammatory protein-2, monocyte chemoattractant protein-1), inflammatory mediators (TNF-alpha, IL-1beta), leukocyte growth and survival factors [granulocyte-macrophage colony-stimulating factor, colony-stimulating factor (CSF)-1, CSF-1 receptor], transforming growth factor-beta, matrix-degrading MMP-9 and MMP-12, and Toll-like receptor (TLR)2, broadly mirroring NF-kappaB activation. No upregulation was observed for MMP-2, urokinase-type plasminogen activator, tissue-type plasminogen activator, and TLRs 3, 4, and 9. In mouse strain comparisons the rank order of susceptibility was Balb/c > C3H/HeJ > 129SvJ > C57BL6. Partition of responses into BAL macrophages vs. lavaged lung strongly implicated macrophages in the inflammatory responses. Strikingly, except for IL-10 and MMP-12, macrophage and lung gene profiles in Balb/c and C57BL/6 mice were very similar. The response pattern we observed suggests that subchronic cigarette smoke exposure may be useful to understand pathogenic mechanisms triggered by cigarette smoke in the lungs including inflammation and alteration of host defense.
Asunto(s)
Inmunidad Innata , Inflamación/fisiopatología , Enfermedades Pulmonares/fisiopatología , FN-kappa B/metabolismo , Péptido Hidrolasas/metabolismo , Humo/efectos adversos , Animales , Líquido del Lavado Bronquioalveolar/citología , Modelos Animales de Enfermedad , Inducción Enzimática , Citometría de Flujo , Inflamación/etiología , Inflamación/inmunología , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , FumarRESUMEN
BACKGROUND: The proteolytic enzyme matrix metalloproteinase (MMP)-9 can degrade structural compounds such as the extracellular matrix and the basement membrane in the airways and lungs. MMP-9 has therefore been implicated in remodelling of the airways and lungs during severe asthma and chronic obstructive pulmonary disease (COPD). METHODS: The effect of the T lymphocyte derived proinflammatory cytokine interleukin (IL)-17 on MMP-9 protein release and activity in the airways was studied in vivo and in vitro. RESULTS: In vivo, intranasal stimulation of mice with IL-17 induced the release of the precursor molecule proMMP-9 in bronchoalveolar lavage (BAL) fluid, associated with a pronounced local accumulation of neutrophils that stained positive for MMP-9. Stimulation with IL-17 also increased the concentration of free soluble MMP-9 that was proteolytically active as determined by a gelatinase substrate assay. The concentration of MMP-9 in BAL fluid had a strong positive correlation with the number of neutrophils; the amount of MMP-9 per neutrophil was not increased by IL-17 stimulation. In vitro, stimulation of mouse neutrophils with IL-17 did not increase the concentration of proMMP-9 in the conditioned medium. CONCLUSION: Local stimulation with IL-17 increases the concentration of biologically active MMP-9 as well as its precursor molecule in mouse airways in vivo. This increase in proteolytic load is probably mainly due to an increased number of neutrophils and not to an increase in the release of MMP-9 from each neutrophil. These findings indicate a link between the T lymphocyte cytokine IL-17 and increased proteolytic load in the airways which may be relevant for chronic inflammatory airway diseases such as severe asthma and COPD.
Asunto(s)
Bronquios/metabolismo , Interleucina-17/farmacología , Metaloproteinasa 9 de la Matriz/metabolismo , Animales , Líquido del Lavado Bronquioalveolar/citología , Endopeptidasas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/metabolismoRESUMEN
Endothelial nitric oxide synthase (eNOS) is an important modulator of angiogenesis and vascular tone [1]. It is stimulated by treatment of endothelial cells in a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent fashion by insulin-like growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF) [2] [3] and is activated by phosphorylation at Ser1177 in the sequence RIRTQS(1177)F (in the single-letter amino acid code) [4]. The protein kinase Akt is an important downstream target of PI 3-kinase [5] [6], regulating VEGF-stimulated endothelial cell survival [7]. Akt phosphorylates substrates within a defined motif [8], which is present in the sequence surrounding Ser1177 in eNOS. Both Akt [5] [6] and eNOS [9] are localized to, and activated at, the plasma membrane. We found that purified Akt phosphorylated cardiac eNOS at Ser1177, resulting in activation of eNOS. Phosphorylation at this site was stimulated by treatment of bovine aortic endothelial cells (BAECs) with VEGF or IGF-1, and Akt was activated in parallel. Preincubation with wortmannin, an inhibitor of Akt signalling, reduced VEGF- or IGF-1-induced Akt activity and eNOS phosphorylation. Akt was detected in immunoprecipitates of eNOS from BAECs, and eNOS in immunoprecipitates of Akt, indicating that the two enzymes associate in vivo. It is thus apparent that Akt directly activates eNOS in endothelial cells. These results strongly suggest that Akt has an important role in the regulation of normal angiogenesis and raise the possibility that the enhanced activity of this kinase that occurs in carcinomas may contribute to tumor vascularization and survival.
Asunto(s)
Óxido Nítrico Sintasa/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas , Secuencia de Aminoácidos , Animales , Sitios de Unión , Bovinos , Línea Celular , Células Cultivadas , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Factores de Crecimiento Endotelial/farmacología , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Linfocinas/farmacología , Datos de Secuencia Molecular , Óxido Nítrico Sintasa/química , Óxido Nítrico Sintasa/genética , Óxido Nítrico Sintasa de Tipo III , Fosforilación , Proteínas Serina-Treonina Quinasas/genética , Proteínas Proto-Oncogénicas c-akt , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal , Transfección , Factor A de Crecimiento Endotelial Vascular , Factores de Crecimiento Endotelial VascularRESUMEN
Post-traumatic infected or noninfected pseudoarthrosis represents one of the therapeutically most resistant problems in contemporary orthopaedics. The incidence of these cases has increased and the problem become even more relevant after mass application of osteosynthetic material was introduced. Without rejecting the classic methods of treatment for infected or noninfected pseudoarthrosis, but with the aim of finding a more functional and more rational therapeutic method, over the past 7 years we have begun to apply a new therapeutic approach in the treatment of pseudoarthrosis, making use of Ilizarov's principle of tensile distraction compression. We have consistently followed the therapeutic schema, applying the method which has been devised at the Kurgan Scientific Research Institute of Experimental and Clinical Orthopedics and Traumatology and making use of the external fixator of the original Ilizarov construction. The basic theoretical postulate on which our entire work has been based is: Dedifferentiation of polyblast cells under the influence of compressive and tensile forces (in rigid fixation conditions) into osteogenic cells. We have treated 168 cases of pseudoarthrosis. After stress compression 59. The average time of fixation was 17,250 days. All patients were ambulatory as early as the second postoperative day with full weight bearing of the affected extremity. Taking into consideration our experiences, we may say that we have been greatly encouraged by our results as they indicated that we were right to continue our work along the same lines.