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Cellular senescence is a stress-response mechanism implicated in various physiological processes, diseases, and aging. Current detection approaches have partially addressed the issue of senescent cell identification in clinical specimens. Effective methodologies enabling precise isolation or live tracking of senescent cells are still lacking. In-depth analysis of truly senescent cells is, therefore, an extremely challenging task. We report (1) the synthesis and validation of a fluorophore-conjugated, Sudan Black-B analog (GLF16), suitable for in vivo and in vitro analysis of senescence by fluorescence microscopy and flow cytometry and (2) the development and application of a GLF16-carrying micelle vector facilitating GLF16 uptake by living senescent cells in vivo and in vitro. The compound and the applied methodology render isolation of senescent cells an easy, rapid, and precise process. Straightforward nanocarrier-mediated GLF16 delivery in live senescent cells comprises a unique tool for characterization of senescence at an unprecedented depth.
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Senescência Celular , Indicadores e Reagentes , Citometria de FluxoRESUMO
In healthy humans, cerebral oxygen desaturation during exercise affects motor unit recruitment, while oxygen supplementation enhances cerebral oxygenation and work capacity. It remains unknown whether in patients with chronic obstructive pulmonary disease (COPD), the well-documented improvement in exercise tolerance with oxygen supplementation may also be partly due to the increase in cerebral oxygenation. Using near infrared spectroscopy, we measured both frontal cerebral cortex blood flow (CBF) using indocyanine green dye and cerebrovascular oxygen saturation (S(t,O(2))) in 12 COPD patients during constant-load exercise to exhaustion at 75% of peak capacity. Subjects exercised while breathing air, 100% oxygen or normoxic heliox, the latter two in balanced order. Time to exhaustion while breathing air was less than for either oxygen or heliox (mean±sem 394±35 versus 670±43 and 637±46 s, respectively). Under each condition, CBF increased from rest to exhaustion. At exhaustion, CBF was higher while breathing air and heliox than oxygen (30.9±2.3 and 31.3±3.5 versus 26.6±3.2 mL·min(-1) per 100 g, respectively), compensating for the lower arterial oxygen content (C(a,O(2))) in air and heliox, and leading to similar cerebral cortex oxygen delivery (CQ(O(2)) for air was 5.3±0.4, for oxygen was 5.5±0.6 and for heliox was 5.6±1.0 mL O(2) per min per 100 g). In contrast, end-exercise S(t,O(2)) was greater while breathing oxygen compared with air or heliox (67±4 versus 57±3 and 53±3%, respectively), reflecting C(a,O(2)) rather than CQ(O(2)). Prolonged time to exhaustion by breathing oxygen and heliox, despite these having a similar CQ(O(2)) to air, a lower S(t,O(2)) with heliox than oxygen, and yet similar endurance time and similar S(t,O(2)) in air and heliox despite greater endurance with heliox, do not support the hypothesis that an improvement in cerebral cortex oxygen availability plays a contributing role in increasing exercise capacity with oxygen or heliox in patients with COPD.
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Córtex Cerebral/fisiologia , Tolerância ao Exercício/fisiologia , Exercício Físico/fisiologia , Oxigênio/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Gasometria , Débito Cardíaco , Circulação Cerebrovascular , Hélio/farmacologia , Hemodinâmica , Humanos , Concentração de Íons de Hidrogênio , Pessoa de Meia-Idade , Oximetria , Oxigênio/farmacologia , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
INTRODUCTION: Gene expression profiling was performed via DNA microarrays in leukocytes from critically ill trauma patients nonseptic upon admission to the ICU, who subsequently developed either sepsis (n = 2) or severe sepsis and acute respiratory distress syndrome (n = 3). By comparing our results with published expression profiling studies in animal models of sepsis and lung injury, we found aquaporin-1 to be differentially expressed across all studies. Our aim was to determine how the water channel aquaporin-1 is involved in regulating the immune response in critically ill patients during infection acquired in the ICU. METHODS: Following the results of the initial genetic screening study, we prospectively followed aquaporin-1 leukocyte expression patterns in patients with ICU-acquired sepsis who subsequently developed septic shock (n = 16) versus critically ill patients who were discharged without developing sepsis (n = 13). We additionally determined aquaporin-1 expression upon lipopolysaccharide (LPS) exposure and explored functional effects of aquaporin-1 induction in polymorphonuclear granulocytes (PMNs). RESULTS: Leukocyte aquaporin-1 expression was induced at the onset of sepsis (median 1.71-fold increase; interquartile range: 0.99 to 2.42, P = 0.012 from baseline) and was further increased upon septic shock (median 3.00-fold increase; interquartile range: 1.20 to 5.40, P = 0.023 from sepsis, Wilcoxon signed-rank test); no difference was observed between baseline and discharge in patients who did not develop sepsis. Stimulation of PMNs by LPS led to increased expression of aquaporin-1 in vitro, which could be abrogated by the NF-κB inhibitor EF-24. PMN hypotonic challenge resulted in a transient increase of the relative cell volume, which returned to baseline after 600 seconds, while incubation in the presence of LPS resulted in persistently increased cell volume. The latter could be abolished by blocking aquaporin-1 with mercury and restored by incubation in ß-mercaptoethanol, which abrogated the action of mercury inhibition. CONCLUSIONS: Aquaporin-1 is induced in leukocytes of patients with ICU-acquired sepsis and exhibits higher expression in septic shock. This phenomenon may be due to LPS-triggered NF-κB activation that can also lead to alterations in plasma membrane permeability.
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Aquaporina 1/biossíntese , Perfilação da Expressão Gênica/métodos , Leucócitos/metabolismo , Sepse/diagnóstico , Sepse/metabolismo , Adulto , Idoso , Aquaporina 1/genética , Células Cultivadas , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Sepse/genéticaRESUMO
Chronic pain is a very common problem in patients with spinal cord injury (SCI) as it affects 80% of these patients, which negatively affects their quality of life. Despite many advantages that exist in the management of any type of pain (neuropathic, nociceptive, mixed) in these patients, there is no cure, and the analgesic effect of some treatments is inadequate. This study aims to conduct an evidence-based systematic review regarding the various interventions used for the management of pain after SCI. The PubMed, Physiotherapy Evidence Database (PEDro), and Cochrane Library databases were searched from 1969 to 2023. The risk of bias was assessed using the PEDro scoring system. A total of 57 studies met the inclusion criteria and were included in this systematic review. Among the different interventions at present, 18 studies examined the role of oral medications, 11 studies examined the role of minimally invasive methods (injection and infusion), 16 studies investigated physiotherapy and alternative treatments, and 12 studies examined the role of repetitive transcranial magnetic stimulation (rTMS), transcranial direct current stimulation (tDCS), and cranial electrotherapy stimulation (CES) in the management of pain in patients after SCI. Gabapentin and pregabalin are very effective in managing chronic neuropathic pain after SCI, and pregabalin also seems to reduce anxiety and sleep disturbances in the patients. It is noteworthy that lamotrigine, valproate, and carbamazepine do not have an analgesic effect, but mirogabalin is a novel and promising drug. Antidepressants (selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors) did not reduce the pain of the patients, although some studies showed an efficacy of amitriptyline especially in depressed patients and tramadol should be considered short-term with caution. Also, tDCS and rTMS reduced pain. Moreover, botulinum toxin type A, lidocaine, ketamine, and intrathecal baclofen significantly reduced pain intensity, although the sample of the studies was small. Physiotherapy and alternative treatments seem to relieve pain, and transcutaneous electrical nerve stimulation had the greatest reduction of pain intensity. In conclusion, several pharmaceutical and non-pharmaceutical methods exist, which can reduce pain in patients after SCI. The type of intervention can be considered by the physician depending on the patients' preference, age, medical history, type of pain, and associated symptoms. However, more studies with greater samples and with better methodological quality should be conducted.
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Since recent evidence indicates a requirement for epithelial nuclear factor (NF)-κB signaling in lung tumorigenesis, we investigated the impact of the NF-κB inhibitor bortezomib on lung tumor promotion and growth. We used an experimental model in which wild-type mice or mice expressing an NF-κB reporter received intraperitoneal urethane (1 g/kg) followed by twice weekly bortezomib (1 mg/kg) during distinct periods of tumor initiation/progression. Mice were serially assessed for lung NF-κB activation, inflammation and carcinogenesis. Short-term proteasome inhibition with bortezomib did not impact tumor formation but retarded the growth of established lung tumors in mice via effects on cell proliferation. In contrast, long-term treatment with bortezomib resulted in significantly increased lung tumor number and size. This tumor-promoting effect of prolonged bortezomib treatment was associated with perpetuation of urethane-induced inflammation and chronic upregulation of interleukin-1ß and proinflammatory C-X-C motif chemokine ligands (CXCL) 1 and 2 in the lungs. In addition to airway epithelium, bortezomib inhibited NF-κB in pulmonary macrophages in vivo, presenting a possible mechanism of tumor amplification. In this regard, RAW264.7 macrophages exposed to bortezomib showed increased expression of interleukin-1ß, CXCL1 and CXCL2. In conclusion, although short-term bortezomib may exert some beneficial effects, prolonged NF-κB inhibition accelerates chemical lung carcinogenesis by perpetuating carcinogen-induced inflammation. Inhibition of NF-κB in pulmonary macrophages appears to play an important role in this adverse process.
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Antineoplásicos/farmacologia , Ácidos Borônicos/farmacologia , Neoplasias Pulmonares/patologia , NF-kappa B/antagonistas & inibidores , Pirazinas/farmacologia , Animais , Bortezomib , Linhagem Celular , Linhagem Celular Tumoral , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/metabolismo , Camundongos , Camundongos Endogâmicos BALB CRESUMO
INTRODUCTION: Diabetic patients may develop acute lung injury less often than non-diabetics; a fact that could be partially ascribed to the usage of antidiabetic drugs, including metformin. Metformin exhibits pleiotropic properties which make it potentially beneficial against lung injury. We hypothesized that pretreatment with metformin preserves alveolar capillary permeability and, thus, prevents ventilator-induced lung injury. METHODS: Twenty-four rabbits were randomly assigned to pretreatment with metformin (250 mg/Kg body weight/day per os) or no medication for two days. Explanted lungs were perfused at constant flow rate (300 mL/min) and ventilated with injurious (peak airway pressure 23 cmH2O, tidal volume ≈17 mL/Kg) or protective (peak airway pressure 11 cmH2O, tidal volume ≈7 mL/Kg) settings for 1 hour. Alveolar capillary permeability was assessed by ultrafiltration coefficient, total protein concentration in bronchoalveolar lavage fluid (BALF) and angiotensin-converting enzyme (ACE) activity in BALF. RESULTS: High-pressure ventilation of the ex-vivo lung preparation resulted in increased microvascular permeability, edema formation and microhemorrhage compared to protective ventilation. Compared to no medication, pretreatment with metformin was associated with a 2.9-fold reduction in ultrafiltration coefficient, a 2.5-fold reduction in pulmonary edema formation, lower protein concentration in BALF, lower ACE activity in BALF, and fewer histological lesions upon challenge of the lung preparation with injurious ventilation. In contrast, no differences regarding pulmonary artery pressure and BALF total cell number were noted. Administration of metformin did not impact on outcomes of lungs subjected to protective ventilation. CONCLUSIONS: Pretreatment with metformin preserves alveolar capillary permeability and, thus, decreases the severity of ventilator-induced lung injury in this model.
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Metformina/farmacologia , Lesão Pulmonar Induzida por Ventilação Mecânica/prevenção & controle , Animais , Líquido da Lavagem Broncoalveolar/química , Permeabilidade Capilar , Modelos Animais de Doenças , Técnicas In Vitro , Masculino , Edema Pulmonar/prevenção & controle , Coelhos , Volume de Ventilação PulmonarRESUMO
BACKGROUND: Autonomic dysfunction is present early in the course of COPD, and is associated with adverse outcomes. We utilized heart rate recovery, a simple and validated index of autonomic balance, to investigate the effects of exercise training on autonomic dysfunction in patients with COPD. METHODS: We evaluated 45 stable subjects with COPD who participated in a 36-session exercise-based cardiopulmonary rehabilitation program. Subjects underwent maximal cardiopulmonary exercise testing at baseline and after completion of the rehabilitation program. We recorded exercise testing parameters and heart rate during rest, exercise, and recovery. Heart rate recovery was calculated as heart rate at peak exercise minus heart rate at the first minute of recovery. RESULTS: Thirty-nine subjects (age 66.3 ± 7.8 y, 90% male, body mass index 27.1 ± 4.1 kg/m(2), FEV(1) 45.7 ± 18.7%) completed the program. In these subjects, heart rate recovery increased from 16.2 ± 8.0 beats/min to 18.4 ± 8.4 beats/min (P = .01), resting heart rate decreased from 88.0 ± 10.7 beats/min to 83.3 ± 10.5 beats/min (P = .004), and heart rate at anaerobic threshold decreased from 109.0 ± 12.5 beats/min to 105.5 ± 11.7 beats/min (P = .040). In addition, oxygen consumption (V(O(2))) increased from 14.3 ± 3.7 mL/kg/min to 15.2 ± 3.8 mL/kg/min at peak exercise, and from 9.7 ± 2.4 mL/kg/min to 10.4 ± 2.6 mL/kg/min at anaerobic threshold (both P = .02), while the V(O(2))/t slope increased from -0.32 ± 0.16 mL/kg/min(2) to -0.38 ± 0.19 mL/kg/min(2) (P = .003). Parameters of ventilatory performance improved also. CONCLUSIONS: In subjects with COPD, exercise-based rehabilitation improves heart rate recovery, modestly though, which indicates a degree of attenuated autonomic dysfunction. Exercise and muscular oxidative capacity, as expressed by V(O(2))/t slope, is also improved.
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Frequência Cardíaca/fisiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/reabilitação , Idoso , Sistema Nervoso Autônomo/fisiopatologia , Teste de Esforço , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Consumo de Oxigênio/fisiologia , Troca Gasosa Pulmonar/fisiologia , Testes de Função RespiratóriaRESUMO
Dizziness is one of the most common symptoms encountered by physicians daily. It is divided into four categories: vertigo, disequilibrium, presyncope, and psychogenic dizziness. It is essential to distinguish these four symptoms because the causes, prognosis, and treatment differ. Vertigo constitutes a disease of the central or peripheral nervous system. Central origin vertigo may be a life-threatening situation and must be detected as soon as possible because it includes diseases such as stroke, hemorrhage, tumors, and multiple sclerosis. Peripheral origin vertigo includes benign diseases, which may be fully treatable such as vestibular migraine, benign paroxysmal positional vertigo, vestibular neuritis, Ménière's disease, and cervical vertigo. The HINTS (head impulse, nystagmus, test of skew) examination is essential to distinguish central from peripheral causes. A detailed history including the duration of vertigo (episodic or continuous), its trigger, and a clinical examination step by step following the appropriate protocol could help to make a definite and accurate diagnosis and treatment. Due to a lack of expertise in dizziness and inappropriate treatment, many patients are admitted to dizziness clinics with long-standing dizziness. A holistic treatment combining medications, vestibular rehabilitation, physiotherapy, and psychotherapy should be initiated to improve the quality of life of these patients. So, this review aims to recommend a clinical protocol for approaching a dizzy patient with vertigo and to present in detail the epidemiology, pathophysiology, symptoms, diagnosis, and contemporary treatments of all causes of vertigo.
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During maximal hypoxic exercise, a reduction in cerebral oxygen delivery may constitute a signal to the central nervous system to terminate exercise. We investigated whether the rate of increase in frontal cerebral cortex oxygen delivery is limited in hypoxic compared to normoxic exercise. We assessed frontal cerebral cortex blood flow using near-infrared spectroscopy and the light-absorbing tracer indocyanine green dye, as well as frontal cortex oxygen saturation (S(tO2)%) in 11 trained cyclists during graded incremental exercise to the limit of tolerance (maximal work rate, WRmax) in normoxia and acute hypoxia (inspired O2 fraction (F(IO2)), 0.12). In normoxia, frontal cortex blood flow and oxygen delivery increased (P < 0.05) from baseline to sub-maximal exercise, reaching peak values at near-maximal exercise (80% WRmax: 287 ± 9 W; 81 ± 23% and 75 ± 22% increase relative to baseline, respectively), both leveling off thereafter up to WRmax (382 ± 10 W). Frontal cortex S(tO2)% did not change from baseline (66 ± 3%) throughout graded exercise. During hypoxic exercise, frontal cortex blood flow increased (P = 0.016) from baseline to sub-maximal exercise, peaking at 80% WRmax (213 ± 6 W; 60 ± 15% relative increase) before declining towards baseline at WRmax (289 ± 5 W). Despite this, frontal cortex oxygen delivery remained unchanged from baseline throughout graded exercise, being at WRmax lower than at comparable loads (287 ± 9 W) in normoxia (by 58 ± 12%; P = 0.01). Frontal cortex S(tO2)% fell from baseline (58 ± 2%) on light and moderate exercise in parallel with arterial oxygen saturation, but then remained unchanged to exhaustion (47 ± 1%). Thus, during maximal, but not light to moderate, exercise frontal cortex oxygen delivery is limited in hypoxia compared to normoxia. This limitation could potentially constitute the signal to limit maximal exercise capacity in hypoxia.
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Atletas , Córtex Cerebral/irrigação sanguínea , Córtex Cerebral/metabolismo , Exercício Físico/fisiologia , Hipóxia/metabolismo , Consumo de Oxigênio/fisiologia , Adulto , Velocidade do Fluxo Sanguíneo/fisiologia , Circulação Cerebrovascular/fisiologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Inspiratory resistive breathing (IRB) induces cytokine expression in the diaphragm. The mechanism of this cytokine induction remains elusive. The roles of MAPKs and NF-κB and the impact of oxidative stress in IRB-induced cytokine upregulation in the diaphragm were studied. Wistar rats were subjected to IRB (50% of maximal inspiratory pressure) via a two-way nonrebreathing valve for 1, 3, or 6 h. Additional groups of rats subjected to IRB for 6 h were randomly assigned to receive either solvent or N-acetyl-cysteine (NAC) or inhibitors of NF-κB (BAY-11-7082), ERK1/2 (PD98059), and P38 MAPK (SB203580) to study the effect of oxidative stress, NF-κB, and MAPKs in IRB-induced cytokine upregulation in the diaphragm. Quietly breathing animals served as controls. IRB upregulated cytokine (IL-6, TNF-α, IL-10, IL-2, IL-1ß) protein levels in the diaphragm and resulted in increased activation of MAPKs (P38, ERK1/2) and NF-κB. Inhibition of NF-κB and ERK1/2 blunted the upregulation of all cytokines except that of IL-6, which was further increased. P38 inhibition attenuated all cytokine (including IL-6) upregulation. Both P38 and ERK1/2 inhibition decreased NF-κB/p65 subunit phosphorylation. NAC pretreatment blunted IRB-induced cytokine upregulation in the diaphragm and resulted in decreased ERK1/2, P38, and NF-κB/p65 phosphorylation. In conclusion, IRB-induced cytokine upregulation in the diaphragm is under the regulatory control of MAPKs and NF-κB. IL-6 is regulated differently from all other cytokines through a P38-dependent and NF-κB independent pathway. Oxidative stress is a stimulus for IRB-induced cytokine upregulation in the diaphragm.
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Resistência das Vias Respiratórias , Citocinas/metabolismo , Diafragma/enzimologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Inalação , NF-kappa B/metabolismo , Estresse Oxidativo , Trabalho Respiratório , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Antioxidantes/farmacologia , Gasometria , Diafragma/efeitos dos fármacos , Diafragma/imunologia , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , NF-kappa B/antagonistas & inibidores , Estresse Oxidativo/efeitos dos fármacos , Fosforilação , Pressão , Inibidores de Proteínas Quinases/farmacologia , Ratos , Ratos Wistar , Fatores de Tempo , Regulação para Cima , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidoresRESUMO
Emerging evidence indicates that, besides dyspnea relief, an improvement in locomotor muscle oxygen delivery may also contribute to enhanced exercise tolerance following normoxic heliox (replacement of inspired nitrogen by helium) administration in patients with chronic obstructive pulmonary disease (COPD). Whether blood flow redistribution from intercostal to locomotor muscles contributes to this improvement currently remains unknown. Accordingly, the objective of this study was to investigate whether such redistribution plays a role in improving locomotor muscle oxygen delivery while breathing heliox at near-maximal [75% peak work rate (WR(peak))], maximal (100%WR(peak)), and supramaximal (115%WR(peak)) exercise in COPD. Intercostal and vastus lateralis muscle perfusion was measured in 10 COPD patients (FEV(1) = 50.5 ± 5.5% predicted) by near-infrared spectroscopy using indocyanine green dye. Patients undertook exercise tests at 75 and 100%WR(peak) breathing either air or heliox and at 115%WR(peak) breathing heliox only. Patients did not exhibit exercise-induced hyperinflation. Normoxic heliox reduced respiratory muscle work and relieved dyspnea across all exercise intensities. During near-maximal exercise, quadriceps and intercostal muscle blood flows were greater, while breathing normoxic heliox compared with air (35.8 ± 7.0 vs. 29.0 ± 6.5 and 6.0 ± 1.3 vs. 4.9 ± 1.2 ml·min(-1)·100 g(-1), respectively; P < 0.05; mean ± SE). In addition, compared with air, normoxic heliox administration increased arterial oxygen content, as well as oxygen delivery to quadriceps and intercostal muscles (from 47 ± 9 to 60 ± 12, and from 8 ± 1 to 13 ± 3 mlO(2)·min(-1)·100 g(-1), respectively; P < 0.05). In contrast, normoxic heliox had neither an effect on systemic nor an effect on quadriceps or intercostal muscle blood flow and oxygen delivery during maximal or supramaximal exercise. Since intercostal muscle blood flow did not decrease by normoxic heliox administration, blood flow redistribution from intercostal to locomotor muscles does not represent a likely mechanism of improvement in locomotor muscle oxygen delivery. Our findings might not be applicable to patients who hyperinflate during exercise.
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Exercício Físico/fisiologia , Hélio/farmacologia , Oxigênio/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Fluxo Sanguíneo Regional/efeitos dos fármacos , Músculos Respiratórios/irrigação sanguínea , Administração por Inalação , Feminino , Hélio/administração & dosagem , Humanos , Perna (Membro)/irrigação sanguínea , Masculino , Pessoa de Meia-Idade , Oxigênio/administração & dosagem , Oxigênio/metabolismo , Troca Gasosa Pulmonar/fisiologia , Fluxo Sanguíneo Regional/fisiologiaRESUMO
BACKGROUND: Exercise training confers beneficial effects on vascular reactivity in patients with chronic heart failure (CHF). This randomized study compares the effects of interval cycle training combined with strength training versus interval training alone on vascular reactivity in CHF patients. METHODS: Twenty-eight consecutive stable CHF patients (23 males, 53 ± 10 years, 28.4 ± 4.1 kg/m(2), left ventricular ejection fraction of 37 ± 12%) were randomly assigned to 3 times' weekly training sessions for 3 months, consisting of a) 40 minutes of interval cycle training (n = 14), versus b) 20 minutes of similar interval training plus 20 minutes of strength training of the quadriceps, hamstrings, muscles of the shoulder and biceps brachialis (n = 14). The work/recovery ratio of each session was 30/60 seconds. The intensity of interval training was set at 50% of the peak workload achieved at the steep ramp test (consisted of a 25-Watt increase on a cycle ergometer every 10 seconds until exhaustion). All patients underwent maximal, symptom-limited cardiopulmonary exercise testing and ultrasound evaluation of vascular reactivity by flow-mediated vasodilation (FMD) before and after the program. RESULTS: A significant improvement in FMD was observed in the combined training group (P = 0.002), in contrast to the interval training alone group (P = NS); the improvement was significantly greater in the combined training than in the interval training alone group (P < .05). Peak oxygen uptake increased significantly and similarly in both groups, in the interval training group (P = .03), and in the combined training group (P = .006). No significant correlation was found between FMD improvement and cardiopulmonary exercise parameters. CONCLUSIONS: A combined high-intensity, interval cycle exercise with strength training induces a greater beneficial effect on vascular reactivity rather than interval exercise training alone in CHF patients.
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Teste de Esforço/métodos , Terapia por Exercício/métodos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/reabilitação , Treinamento Resistido/métodos , Vasodilatação/fisiologia , Adulto , Feminino , Insuficiência Cardíaca/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Cytokines are key players in the biological processes of malignant tumors and special interest has been focused on cytokines exerting tumor and anti-tumor properties, such as vascular endothelial growth factor (VEGF) and Interleukin-18 (IL-18). Aim of this study was to assess IL-18 and VEGF levels in induced sputum of lung cancer patients at diagnosis, and assess their possible association with the histological type of cancer, the stage and the overall patient survival. Seventy six patients with a diagnosis of lung cancer were recruited and were followed up for 48months. Thirteen healthy smokers and 16 healthy non-smokers were used as control groups. VEGF and IL-18 were measured by ELISA in sputum supernatants at the time of diagnosis. Lung cancer patients had significantly higher baseline IL-18 and VEGF levels compared to healthy controls (p<0.001). No difference was found in IL-18 and VEGF levels between the various stages in non-small cell lung cancer (NSCLC) and between limited and extended small cell lung cancer (SCLC). However, the ratio of VEGF/IL-18 was significantly higher in NSCLC compared to SCLC patients (p=0.018). In extended SCLC overall survival was inversely associated with baseline sputum VEGF levels (p=0.034) and estimated mortality risk was 1.14 (95% CI 1.006-1.283) for an increase of 100pg/ml in VEGF levels. Such association was not found regarding baseline IL-18 levels. VEGF levels in induced sputum may have a prognostic role in the survival of SCLC. The ratio VEGF/IL-18 in induced sputum differs between NSCLC and SCLC, indicating differences in angiogenesis mechanisms and/or immunological response in these two major histological types of lung cancer.
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Interleucina-18/metabolismo , Neoplasias Pulmonares/metabolismo , Escarro/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto , Idoso , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Risco , Carcinoma de Pequenas Células do Pulmão/metabolismo , Fumar , Resultado do TratamentoRESUMO
BACKGROUND: Obesity and asthma are characterized by the presence of inflammation. Leptin and adiponectin are circulating hormones produced by adipose tissue that regulate several metabolic and inflammatory functions. We aimed to determine whether obesity influences asthmatic inflammation as well as the contribution of leptin or/and adiponectin to a possible linkage between asthmatic and obesity-related inflammation. MATERIALS AND METHODS: One hundred patients with asthma and 60 healthy controls were studied. Subjects who had a comorbid illness that could interfere with the proposed tests were excluded. All subjects were divided into three groups (normal range, pre-obese, obese) according to the criteria of the current WHO international classification for body mass index (BMI). Possible associations between variables expressing airway inflammation, bronchial hyper-responsiveness, systemic inflammation and obesity, as assessed by BMI, were evaluated. Leptin and adiponectin were also measured and were associated with asthma airway and systemic inflammatory variables to elucidate possible associations. RESULTS: Obese patients had significant higher values of LTE(4) /creatinine in urine compared with pre-obese and normal range ones. In a linear regression model, the only significant associations were those between BMI and LTE(4) /creatinine in urine. Using the same model, log leptin and log adiponectin presented positive and negative associations, respectively with LTE(4) /creatinine in urine. No other significant associations were observed in both patients and healthy subjects. CONCLUSIONS: In a selected cohort of asthmatic patients, obesity is significantly associated with increased urinary leukotriene levels. Alterations of leptin/adiponectin balance may be related to the presence of leukotriene inflammation in obese asthmatic patients.
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Adiponectina/metabolismo , Asma/complicações , Índice de Massa Corporal , Leptina/metabolismo , Obesidade/complicações , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asma/fisiopatologia , Estudos de Casos e Controles , Feminino , Humanos , Inflamação/complicações , Inflamação/fisiopatologia , Leucotrienos/metabolismo , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: The inflammatory influence of prolonged mechanical ventilation in uninjured lungs remains a matter of controversy and largely unexplored in humans. The authors investigated pulmonary inflammation by using exhaled breath condensate (EBC) in mechanically ventilated, brain-injured patients in the absence of acute lung injury or sepsis and explored the potential influence of positive end-expiratory pressure (PEEP). METHODS: Inflammatory EBC markers were assessed in 27 mechanically ventilated, brain-injured patients with neither acute lung injury nor sepsis and in 12 healthy and 8 brain-injured control subjects. Patients were ventilated with 8 ml/kg during zero end-expiratory pressure (ZEEP group, n = 12) or 8 cm H(2)O PEEP (PEEP group, n = 15). EBC was collected on days 1, 3, and 5 of mechanical ventilation to measure pH; interleukins (IL)-10, 1ß, 6, 8, and 12p70; and tumor necrosis factor-α. RESULTS: EBC pH was lower, whereas IL-1ß and tumor necrosis factor-α were greater in both patient groups compared with either control group; IL-6 was higher, whereas IL-10 and IL-12p70 were sporadically higher than in healthy control subjects; no differences were noted between the two patient groups, except for IL-10, which decreased by day 5 during PEEP. Leukocytes, soluble IL-6, and soluble triggering receptor expressed on myeloid cells-1 in blood were constantly higher during zero end-expiratory pressure; EBC cytokines appeared mostly related to soluble IL-8 and inversely related to soluble triggering receptor expressed on myeloid cells-1. CONCLUSIONS: In brain-injured, mechanically ventilated patients with neither acute lung injury nor sepsis, EBC markers appear to indicate the presence of subtle pulmonary inflammation that is mostly unaffected by PEEP. There is evidence for a systemic inflammatory response, especially in patients during zero end-expiratory pressure.
Assuntos
Lesões Encefálicas/complicações , Expiração , Pneumonia/metabolismo , Respiração com Pressão Positiva/métodos , Adulto , Biomarcadores/metabolismo , Testes Respiratórios , Feminino , Humanos , Concentração de Íons de Hidrogênio , Interleucinas/metabolismo , Lesão Pulmonar/complicações , Masculino , Pneumonia/complicações , Sepse/complicações , Fator de Necrose Tumoral alfa/metabolismo , Adulto JovemRESUMO
OBJECTIVE: Recent studies have demonstrated that hydrogen sulfide (H(2)S) is produced within the vessel wall from L-cysteine regulating several aspects of vascular homeostasis. H(2)S generated from cystathione γ-lyase (CSE) contributes to vascular tone; however, the molecular mechanisms underlying the vasorelaxing effects of H(2)S are still under investigation. METHODS AND RESULTS: Using isolated aortic rings, we observed that addition of L-cysteine led to a concentration-dependent relaxation that was prevented by the CSE inhibitors DL-propargylglyicine (PAG) and ß-cyano-l-alanine (BCA). Moreover, incubation with PAG or BCA resulted in a rightward shift in sodium nitroprusside-and isoproterenol-induced relaxation. Aortic tissues exposed to PAG or BCA contained lower levels of cGMP, exposure of cells to exogenous H(2)S or overexpression of CSE raised cGMP concentration. RNA silencing of CSE expression reduced intracellular cGMP levels confirming a positive role for endogenous H(2)S on cGMP accumulation. The ability of H(2)S to enhance cGMP levels was greatly reduced by the nonselective phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine. Finally, addition of H(2)S to a cell-free system inhibited both cGMP and cAMP breakdown. CONCLUSIONS: These findings provide direct evidence that H(2)S acts as an endogenous inhibitor of phosphodiesterase activity and reinforce the notion that this gasotransmitter could be therapeutically exploited.
Assuntos
Sulfeto de Hidrogênio/metabolismo , Inibidores de Fosfodiesterase/metabolismo , Vasodilatação/fisiologia , 1-Metil-3-Isobutilxantina/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Alcinos/farmacologia , Animais , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/fisiologia , Células Clonais , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Cistationina gama-Liase/antagonistas & inibidores , Cistationina gama-Liase/genética , Cistationina gama-Liase/metabolismo , Cisteína/farmacologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Glicina/análogos & derivados , Glicina/farmacologia , Humanos , Técnicas In Vitro , Masculino , RNA Interferente Pequeno/genética , Ratos , Ratos Wistar , Vasodilatação/efeitos dos fármacosRESUMO
RATIONALE: It has been hypothesized that, because of the high work of breathing sustained by patients with chronic obstructive pulmonary disease (COPD) during exercise, blood flow may increase in favor of the respiratory muscles, thereby compromising locomotor muscle blood flow. OBJECTIVES: To test this hypothesis by investigating whether, at the same work of breathing, intercostal muscle blood flow during exercise is as high as during resting isocapnic hyperpnea when respiratory and locomotor muscles do not compete for the available blood flow. METHODS: Intercostal and vastus lateralis muscle perfusion was measured simultaneously in 10 patients with COPD (FEV1 = 50.5 ± 5.5% predicted) by near-infrared spectroscopy using indocyanine green dye. MEASUREMENTS AND MAIN RESULTS: Measurements were made at several exercise intensities up to peak work rate (WRpeak) and subsequently during resting hyperpnea at minute ventilation levels up to those at WRpeak. During resting hyperpnea, intercostal muscle blood flow increased with the power of breathing to 11.4 ± 1.6 ml/min per 100 g at the same ventilation recorded at WRpeak. Conversely, during graded exercise, intercostal muscle blood flow remained unchanged from rest up to 50% WRpeak (6.8 ± 1.3 ml/min per 100 g) and then fell to 4.5 ± 0.8 ml/min per 100 g at WRpeak (P = 0.003). Cardiac output plateaued above 50% WRpeak (8.4 ± 0.1 l/min), whereas vastus lateralis muscle blood flow increased progressively, reaching 39.8 ± 7.1 ml/min per 100 g at WRpeak. CONCLUSIONS: During intense exercise in COPD, restriction of intercostal muscle perfusion but preservation of quadriceps muscle blood flow along with attainment of a plateau in cardiac output represents the inability of the circulatory system to satisfy the energy demands of locomotor and respiratory muscles.
Assuntos
Exercício Físico/fisiologia , Músculos Intercostais/irrigação sanguínea , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Músculo Quadríceps/irrigação sanguínea , Trabalho Respiratório/fisiologia , Idoso , Corantes , Feminino , Hemodinâmica/fisiologia , Humanos , Verde de Indocianina , Músculos Intercostais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Músculo Quadríceps/fisiopatologia , Fluxo Sanguíneo Regional , Testes de Função Respiratória , Espectroscopia de Luz Próxima ao InfravermelhoRESUMO
RATIONALE: Resistive breathing is associated with large negative intrathoracic pressures. Increased mechanical stress induces high-permeability pulmonary edema and lung inflammation. OBJECTIVES: To determine the effects of resistive breathing on the healthy lung. METHODS: Anesthetized rats breathed through a two-way nonrebreathing valve. The inspiratory line was connected to a resistance setting peak inspiratory tracheal pressure at 50% of maximum (inspiratory resistive breathing), while 100% oxygen was supplied to prevent hypoxemia. Quietly breathing animals (100% oxygen) served as controls. Lung injury was evaluated after 3 and 6 hours of resistive breathing. MEASUREMENTS AND MAIN RESULTS: After both 3 and 6 hours of resistive breathing, lung permeability was increased, as assessed by (99m)Tc-diethylenetriaminepentaacetic acid scintigraphy and Evans blue dye extravasation. Tissue elasticity, measured on the basis of static pressure-volume curves and by the low-frequency forced oscillation technique, was also increased. After both 3 and 6 hours of resistive breathing, gravimetric measurements revealed the presence of pulmonary edema and analysis of bronchoalveolar lavage showed increased total protein content, whereas the total cell count was elevated only after 6 hours of resistive breathing. Cytokine levels were assessed in bronchoalveolar lavage fluid and lung tissue by ELISA and were increased after 6 hours compared with controls. Western blot analysis showed early activation of Src kinase via phosphorylation (at 30 min), and Erk1/2 and IκBα (nuclear factor-κB inhibitor) were phosphorylated at 3 and 6 hours. Pathology revealed the presence of lung injury after resistive breathing. CONCLUSIONS: Resistive breathing induces acute lung injury and inflammation.
Assuntos
Lesão Pulmonar Aguda/fisiopatologia , Respiração , Trabalho Respiratório/fisiologia , Lesão Pulmonar Aguda/patologia , Animais , Asma/fisiopatologia , Western Blotting , Líquido da Lavagem Broncoalveolar/química , Permeabilidade Capilar/fisiologia , Contagem de Células , Citocinas/análise , Feminino , Imuno-Histoquímica , Pulmão/patologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Ratos , Ratos Wistar , Estresse MecânicoRESUMO
RATIONALE: IL-5 is a T helper 2 cytokine important in the trafficking and survival of eosinophils. Because eosinophils can be found in malignant pleural effusions (MPE) from mice and humans, we asked whether IL-5 is involved in the pathogenesis of MPE. OBJECTIVES: To determine the role of IL-5 in MPE formation. METHODS: The effects of IL-5 on experimental MPE induced in C57BL/6 mice by intrapleural injection of syngeneic lung (Lewis lung cancer [LLC]) or colon (MC38) adenocarcinoma cells were determined using wild-type (il5(+/+)) and IL-5-deficient (il5â»(/)â») mice, exogenous administration of recombinant mouse (rm) IL-5, and in vivo antibody-mediated neutralization of endogenous IL-5. The direct effects of rmIL-5 on LLC cell proliferation and gene expression in vitro were determined by substrate reduction and microarray. MEASUREMENTS AND MAIN RESULTS: Eosinophils and IL-5 were present in human and mouse MPE, but the cytokine was not detected in mouse (LLC) or human (A549) lung and mouse colon (MC38) adenocarcinoma-conditioned medium, suggesting production by host cells in MPE. Compared with il5(+/+) mice, il5â»(/)â» mice showed markedly diminished MPE formation in response to both LLC and MC38 cells. Exogenous IL-5 promoted MPE formation in il5(+/+) and il5â»(/)â» mice, whereas anti-IL-5 antibody treatment limited experimental MPE in il5(+/+) mice. Exogenous IL-5 had no effects on LLC cell proliferation and gene expression; however, IL-5 was found to be responsible for recruitment of eosinophils and tumor-promoting myeloid suppressor cells to MPE in vivo. CONCLUSIONS: Host-derived IL-5 promotes experimental MPE and may be involved in the pathogenesis of human MPE.
Assuntos
Adenocarcinoma/fisiopatologia , Interleucina-5/fisiologia , Neoplasias Pulmonares/fisiopatologia , Derrame Pleural Maligno/fisiopatologia , Adenocarcinoma/complicações , Animais , Carcinoma Pulmonar de Lewis/complicações , Carcinoma Pulmonar de Lewis/fisiopatologia , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Eosinófilos/fisiologia , Citometria de Fluxo , Perfilação da Expressão Gênica , Humanos , Interleucina-5/análise , Interleucina-5/biossíntese , Interleucina-5/farmacologia , Neoplasias Pulmonares/complicações , Camundongos , Camundongos Endogâmicos C57BL , Derrame Pleural Maligno/induzido quimicamente , Derrame Pleural Maligno/química , Derrame Pleural Maligno/citologiaRESUMO
To determine the epidemiology, risk factors for and outcome of candidaemia in critically ill patients, a matched case-control study was performed in a 25-bed intensive care unit (ICU) from August 2004 to January 2006. Candidaemia occurred in 33 patients; each patient was matched to four controls according to admission illness severity, diagnostic category and length of ICU stay. Candida non-albicans species predominated (67.7%). The presence of acute respiratory distress syndrome (ARDS) was the only independent risk factor for candidaemia development (OR, 2.93; 95% CI 1.09-7.81, P = 0.032). Mortality was 60.6% among patients with candidaemia and 22% among controls (P < 0.001). The presence of candidaemia (OR, 9.37; 95% CI 3.48-25.26, P < 0.001) and the illness severity on admission (acute physiologic and chronic health evaluation II score, OR, 1.17; 95% CI 1.12-1.24, P < 0.001) were independently associated with mortality. Among candidaemic patients, risk factors for mortality were the severity of organ dysfunction (sequential organ failure assessment score, OR, 1.57; 95% CI 1.00-2.46, P = 0.05) and a low serum albumin level (OR, 0.74; 95% CI 0.59-0.94, P = 0.012) both of them occurred on candidaemia onset. We conclude that in critically ill patients matched for illness severity and length of ICU stay, the only independent risk factor for candidaemia was the presence of ARDS. Mortality was independently associated with acquisition of candidaemia and with the illness severity at candidaemia onset.