RESUMO
INTRODUCTION: In septic shock, mitochondrial dysfunction, and hypoperfusion are the main triggers of multi-organ failure. Little is known about the crosstalk between mitochondrial dysfunction and hemodynamic alterations, especially in the post-resuscitation phase. Here, we assess whether hypoperfusion and lactate levels are associated with oxygen consumption linked to mitochondrial bioenergetic activity in lymphocytes of patients admitted with septic shock. PATIENTS AND METHODS: Prospective cohort study in patients with septic shock defined as the requirement of vasopressors to maintain a mean arterial pressure 65 mm Hg after initial fluid administration. Basal mitochondrial and Complex I respiration was measured to evaluate mitochondrial activity. Both variables and capillary refill time were compared with arterial lactate post-fluid resuscitation. We also compared mitochondrial activity measurements between patients with and without hypoperfusion status. RESULTS: A total of 90 patients were included in analysis. The median arterial lactate at the time of septic shock diagnosis was 2.0 mmol/Dl (IQR 1.3-3.0). Baseline respiration at the time of septic shock diagnosis was correlated with lactate (Spearman -0.388, 95% CI -0.4893 to -0.1021; Pâ=â0.003), as well as Complex I respiration (Spearman -0.403, 95% CI -0.567 to -0.208; Pâ<â0.001). Patients with hypoperfusion status had no difference in basal respiration when compared with patients who did not have hypoperfusion status (Pâ=â0.22) nor in Complex I respiration (Pâ=â0.09). CONCLUSION: Changes in lymphocytic mitochondrial metabolism are associated with post-resuscitation arterial lactate in septic shock; however, they are not associated with the presence of a hypoperfusional status. In this scenario, it is therefore suggested that systemic perfusion and mitochondrial metabolism have different courses.
Assuntos
Hiperlactatemia/etiologia , Linfócitos/fisiologia , Doenças Mitocondriais/etiologia , Consumo de Oxigênio/fisiologia , Choque Séptico/complicações , Choque Séptico/fisiopatologia , Idoso , Feminino , Hemodinâmica/fisiologia , Humanos , Hiperlactatemia/diagnóstico , Hiperlactatemia/fisiopatologia , Ácido Láctico/sangue , Masculino , Pessoa de Meia-Idade , Doenças Mitocondriais/sangue , Doenças Mitocondriais/fisiopatologia , Estudos Prospectivos , Ressuscitação , Choque Séptico/sangue , Vasoconstritores/uso terapêuticoRESUMO
The delta-amino acid 5-aminolevulinic acid (ALA), is the precursor of the endogenous photosensitiser Protoporphyrin IX (PpIX), and is currently approved for Photodynamic Therapy (PDT) of certain superficial cancers. However, ALA-PDT is not very effective in diseases in which T-cells play a significant role. Cutaneous T-cell lymphomas (CTCL) is a group of non-Hodgkin malignant diseases, which includes mycosis fungoides (MF) and Sézary syndrome (SS). In previous work, we have designed new ALA esters synthesised by three-component Passerini reactions, and some of them showed higher performance as compared to ALA. This work aimed to determine the efficacy as pro-photosensitisers of five new ALA esters of 2-hydroxy-N-arylacetamides (1f, 1 g, 1 h, 1i and 1 k) of higher lipophilicity than ALA in Myla cells of MF and HuT-78 cells of SS. We have also tested its effectiveness against ALA and the already marketed ALA methyl ester (Me-ALA) and ALA hexyl ester (He-ALA). Both cell Myla and SS cells were effectively and equally photoinactivated by ALA-PDT. Besides, the concentration of ALA required to induce half the maximal porphyrin synthesis was 209 µM for Myla and 169 µM for HuT-78 cells. As a criterion of efficacy, we calculated the concentration of the ALA derivatives necessary to induce half the plateau porphyrin values obtained from ALA. These values were achieved at concentrations 4 and 12 times lower compared to ALA, according to the derivative used. For He-ALA, concentrations were 24 to 25 times lower than required for ALA for inducing comparable porphyrin synthesis in both CTCL cells. The light doses for inducing 50% of cell death (LD50) for He-ALA, 1f, 1 g, 1 h and 1i were around 18 and 25 J/cm2 for Myla and HuT-78 cells respectively, after exposure to 0.05 mM concentrations of the compounds. On the other hand, the LD50s for the compound 1 k were 40 and 57 J/cm2 for Myla and HuT-78, respectively. In contrast, 0.05 mM of ALA and Me-ALA did not provoke photokilling since the concentration employed was far below the porphyrin saturation point for these compounds. Our results suggest the potential use of ALA derivatives for topical application in PDT treatment of MF and extracorporeal PDT for the depletion of activated T-cells in SS.
Assuntos
Ácido Aminolevulínico/análogos & derivados , Fármacos Fotossensibilizantes/farmacologia , Ácido Aminolevulínico/farmacologia , Ácido Aminolevulínico/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos da radiação , Humanos , Luz , Linfócitos/efeitos dos fármacos , Linfócitos/metabolismo , Linfócitos/fisiologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/química , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
In agreement with other fungal infections, immunoprotection in pulmonary paracoccidioidomycosis (PCM) is mediated by Th1/Th17 cells whereas disease progression by prevalent Th2/Th9 immunity. Treg cells play a dual role, suppressing immunity but also controlling excessive tissue inflammation. Our recent studies have demonstrated that the enzyme indoleamine 2,3 dioxygenase (IDO) and the transcription factor aryl hydrocarbon receptor (AhR) play an important role in the immunoregulation of PCM. To further evaluate the immunomodulatory activity of AhR in this fungal infection, Paracoccidioides brasiliensis infected mice were treated with two different AhR agonists, L-Kynurenin (L-Kyn) or 6-formylindole [3,2-b] carbazole (FICZ), and one AhR specific antagonist (CH223191). The disease severity and immune response of treated and untreated mice were assessed 96 hours and 2 weeks after infection. Some similar effects on host response were shared by FICZ and L-Kyn, such as the reduced fungal loads, decreased numbers of CD11c+ lung myeloid cells expressing activation markers (IA, CD40, CD80, CD86), and early increased expression of IDO and AhR. In contrast, the AhR antagonist CH223191 induced increased fungal loads, increased number of pulmonary CD11c+ leukocytes expressing activation markers, and a reduction in AhR and IDO production. While FICZ treatment promoted large increases in ILC3, L-Kyn and CH223191 significantly reduced this cell population. Each of these AhR ligands induced a characteristic adaptive immunity. The large expansion of FICZ-induced myeloid, lymphoid, and plasmacytoid dendritic cells (DCs) led to the increased expansion of all CD4+ T cell subpopulations (Th1, Th2, Th17, Th22, and Treg), but with a clear predominance of Th17 and Th22 subsets. On the other hand, L-Kyn, that preferentially activated plasmacytoid DCs, reduced Th1/Th22 development but caused a robust expansion of Treg cells. The AhR antagonist CH223191 induced a preferential expansion of myeloid DCs, reduced the number of Th1, Th22, and Treg cells, but increased Th17 differentiation. In conclusion, the present study showed that the pathogen loads and the immune response in pulmonary PCM can be modulated by AhR ligands. However, further studies are needed to define the possible use of these compounds as adjuvant therapy for this fungal infection.
Assuntos
Diferenciação Celular/imunologia , Ligantes , Linfócitos/fisiologia , Paracoccidioidomicose/imunologia , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/imunologia , Índice de Gravidade de Doença , Animais , Diferenciação Celular/genética , Imunidade Inata , Imunomodulação , Pulmão/imunologia , Pneumopatias Fúngicas/imunologia , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Células Th1/imunologia , Células Th17/imunologiaRESUMO
The inflammatory response is a complex process that relies on interactions among multiple endocrine and immune modulators. Studies incorporating time-related and integrative endocrine and immune responses to an immune challenge might shed light on the characterization of the phases of the inflammatory response in anurans. The present study investigated time-related changes (1, 3, 6, and 18 h post-challenge) in plasma corticosterone (CORT), melatonin (MEL) and testosterone (T) levels, phagocytosis percentage (PP), plasma bacterial killing ability (BKA), and neutrophil to lymphocyte ratio (NLR) following a lipopolysaccharide (LPS) immune challenge in Rhinella diptycha toads. Our results showed the response to LPS injection was characterized by increased CORT, PP, BKA, and NLR, with a concomitant decrease in plasma MEL and T. Increased CORT was more pronounced at 6 and 18 h, while increased NLR was observed only 18 h post-LPS injection. Meanwhile, plasma MEL and T decreased independently of the time post-LPS injection. Additionally, toads in better body condition showed higher BKA and PP in the LPS-treated group, regardless of the time postinjection. Our results show that toads (R. diptycha) were sensitive to the LPS challenge, mounting an inflammatory response, which started quickly (after 1 h) and developed over time and was influenced by body condition. These results demonstrate a time-related hormonal and immune variation as a consistent pattern of activation of the immune system, as well as of hypothalamic-pituitary-adrenal/interrenal and immune-pineal axes following an immune challenge more deeply studied in mammals, suggesting the evolutionary conservation of the regulatory mechanisms for tetrapod vertebrates.
Assuntos
Bufonidae/imunologia , Corticosterona/sangue , Imunomodulação/efeitos dos fármacos , Lipopolissacarídeos/toxicidade , Melatonina/sangue , Animais , Atividade Bactericida do Sangue , Inflamação/induzido quimicamente , Inflamação/imunologia , Linfócitos/fisiologia , Masculino , Neutrófilos/fisiologia , Fagocitose , Testosterona/sangueRESUMO
This study aimed to investigate the impact of a 16-week dance-based aerobic exercise program on lymphocyte function in healthy and type 2 diabetes mellitus (T2DM) women. We enrolled 23 women: 11 with T2DM and 12 non-diabetic controls. Initially, we performed anthropometry and body composition measurements, afterwards, plasma levels of C-reactive protein, lipids, and glucose were determined. We used flow cytometry to measure the CD25 and CD28 expression in circulating lymphocytes, T-regulatory (Treg) cell percentage, lymphocyte proliferation, and cytokines released by cultured lymphocytes. The T2DM group had a lower proportion of CD28+ cells and a higher percentage of Treg lymphocytes and proliferative capacity at the baseline compared with the control group. After 16 weeks of the program, differences in lymphocytes between the T2DM and the control groups disappeared. The dance program promoted IL-10 increase in both groups. We found decreased IL-4, IL-2, and IL-6 secretion in lymphocytes from the control group and increased IL-17 secretion and IL-10/IL-17 ratio in the T2DM group after the program. The program promoted marked changes in lymphocytes in diabetic women, leading to a balance between the different profiles.
Assuntos
Antígenos CD28/sangue , Dança/fisiologia , Diabetes Mellitus Tipo 2/sangue , Exercício Físico/fisiologia , Subunidade alfa de Receptor de Interleucina-2/sangue , Linfócitos/metabolismo , Idoso , Glicemia/análise , Composição Corporal , Proteína C-Reativa/análise , Estudos de Casos e Controles , Proliferação de Células , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/imunologia , Feminino , Humanos , Interleucinas/sangue , Lipídeos/sangue , Linfócitos/citologia , Linfócitos/fisiologia , Pessoa de Meia-Idade , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/fisiologia , Fatores de TempoRESUMO
Hydro-distilled essential oil from leaves of Xylopia laevigata was characterized by GC-MS. Twenty-seven components were identified and the oil's major constituents comprised germacrene D, bicyclogermacrene, (E)-caryophyllene and germacrene B. The cytotoxicity of the essential oil of X. laevigata (EOXL), determined by MTT and mitotic index methods in cultured human lymphocytes was observed in all tested concentrations. Cultures treated with EOXL demonstrated significant increase in the frequencies of micronuclei in the cytokinesis-block micronucleus assay (CBMN) and reduction of the cytokinesis-block proliferation index (CBPI) rates. Results demonstrated the cytostatic and mutagenic effects of EOXL, the latter for the first time.
Assuntos
Citostáticos/farmacologia , Linfócitos/efeitos dos fármacos , Mutagênicos/farmacologia , Óleos Voláteis/farmacologia , Xylopia/química , Células Cultivadas , Citostáticos/química , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Linfócitos/fisiologia , Testes para Micronúcleos , Mutagênicos/química , Óleos Voláteis/química , Óleos Voláteis/toxicidade , Folhas de Planta/química , Plantas Medicinais/química , Sesquiterpenos Policíclicos/análise , Sesquiterpenos de Germacrano/análiseRESUMO
La función de las amígdalas siempre ha sido discutida, desde afirmar que no tenían funcionalidad, hasta la actualidad que se plantea un papel inmunológico, con actividad linfocitaria de defensa, debido a la localización de linfocitos en el tejido de las amígdalas. Este artículo de actualización pretende describir desde la embriología, histología, fisiología, patología y estomatología, el rol que desempeñan las mismas en su papel inmunológico ante la acción de agentes patógenos. Se destaca la acción conjunta de las amígdalas palatinas, amígdalas faríngeas o adenoides, amígdalas peritubarias, amígdalas linguales y todo el resto de tejido linfático que conforman el anillo linfático faríngeo o anillo de Waldeyer, ya que cumplen un rol determinante en la defensa del organismo (AU)
The function of the tonsils has always been debated, from stating that they had no functionality, to the present day that an immunological role is proposed, with lymphocyte defense activity, due to the location of lymphocytes in the tissue of the tonsils. This update article aims to describe from embryology, histology, physiology, pathology and stomatology, the role they play in their immunological role against the action of pathogens. The joint action of the palatine tonsils, pharyngeal or adenoid tonsils, peritubal tonsils, lingual tonsils and all the rest of the lymphatic tissue that make up the pharyngeal lymphatic ring or Waldeyer's ring is highlighted, since they play a decisive role in the defense of the organism (AU)
Assuntos
Humanos , Tonsila Palatina/imunologia , Tonsila Faríngea/imunologia , Tecido Linfoide , Imunoglobulinas/fisiologia , Linfócitos/fisiologia , Doenças da Boca/imunologiaRESUMO
In December 2019, a new coronavirus was identified as the cause of an outbreak of pneumonia and respiratory distress in Wuhan, China. It was declared pandemic in March 2020. It is important to know predictors of poor outcomes in order to optimize the strategies of care in newly diagnosed patients. The neutrophil to lymphocyte ratio (NLR) constitutes a novel prognostic marker for oncologic, cardiovascular and infectious diseases. We aimed to assess its prognostic value in COVID-19. We evaluated a retrospective cohort of 131 patients with COVID-19 from March to May 2020. We analyzed the association of an NLR = 3 with severe COVID-19, baseline characteristics of the population and the mortality rate. The median age was 52 years, and 54% were men. 21 patients presented criteria of severe disease, 9 of them required mechanical ventilation. NLR = 3 was found in 81% (18/21) of severe patients and in 33% (36/110) of mild patients (OR = 8.74. 95% CI 2.74-27.86; p < 0.001). Age and hypertension were associated with severe disease. A mortality rate of 7% (9) was obtained. Seven of the 9 patients who died presented NLR = 3, with a significant association between mortality and NLR = 3 (p = 0.03). NLR could be used in conjunction with other predictors, as an early prognostic marker in COVID-19 given its accessibility and low cost.
En diciembre de 2019 un nuevo coronavirus se identificó como causa de un brote de neumonía y distrés respiratorio en Wuhan, China. En marzo de 2020 fue declarado pandemia. Resulta importante conocer predictores de mala evolución para optimizar estrategias de cuidados. El índice neutrófilo-linfocito (INL) constituye un novedoso marcador pronóstico en enfermedades cardiovasculares, oncológicas e infecciosas. Este trabajo analiza su valor pronóstico en COVID-19. Se evaluó una cohorte retrospectiva de 131 pacientes con COVID-19 confirmado, entre marzo y mayo de 2020. Se analizaron las características basales de la población, la asociación del INL = 3 con COVID-19 grave y la tasa de mortalidad de la enfermedad. La mediana de edad fue de 52 años, 54% fueron hombres. En 21 pacientes se encontraron criterios de gravedad, 9 de ellos requirieron ventilación mecánica. Presentó INL = 3 el 81% (18/21) de los pacientes graves y el 33% (36/110) de los pacientes leves (OR = 8.74. IC del 95%: 2.74-27.86; p < 0.001). La edad y la hipertensión se asociaron con enfermedad grave. La mortalidad observada en la cohorte fue del 7% (9). En 7 de los 9 pacientes fallecidos se observó un INL = 3 (p = 0.03). El INL, en conjunto con otros predictores, podría usarse como un marcador pronóstico temprano dada la alta accesibilidad y el bajo costo de la prueba.
Assuntos
Biomarcadores/sangue , Infecções por Coronavirus/diagnóstico , Linfócitos/fisiologia , Neutrófilos/fisiologia , Pandemias , Pneumonia Viral/diagnóstico , Fatores Etários , Betacoronavirus , COVID-19 , Infecções por Coronavirus/sangue , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/patologia , Feminino , Humanos , Hipertensão/complicações , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia , Pneumonia Viral/sangue , Pneumonia Viral/epidemiologia , Pneumonia Viral/patologia , Prognóstico , Estudos Retrospectivos , SARS-CoV-2 , Índice de Gravidade de DoençaRESUMO
Cane toads (Rhinella marina) were introduced worldwide and have become invasive in multiple locations, representing a major driver of biodiversity loss through competition (food, shelter, territory), predation, and the poisoning of native species. These toads have been used in Australia as a model for studies concerning invasion biology and ecoimmunology, as longer-established (core) and invasion front (edge) populations show altered stress and immune response profiles. Although cane toads were also introduced into the United States in the 1950s, these patterns have yet to be evaluated for the populations spanning Florida. Toads introduced into Florida have dispersed primarily northward along a latitudinal gradient, where they encounter cooler temperatures that may further impact stress and immune differences between core and edge populations. In this study, we sampled cane toads from nine different locations spanning their invasion in Florida. Cane toads from southern populations showed higher plasma bacterial killing ability and natural antibody titers than the toads from the northern populations, indicating they have a better immune surveillance system. Also, southern toads were more responsive to a novel stressor (1 hr restraint), showing a higher increase in corticosterone levels. These results indicate that possible trade-offs have occurred between immune and stress responses as these toads have become established in northern cooler areas in Florida.
Assuntos
Bufo marinus/imunologia , Estresse Fisiológico/imunologia , Animais , Atividade Bactericida do Sangue , Bufo marinus/sangue , Bufo marinus/fisiologia , Corticosterona/sangue , Feminino , Florida , Testes de Hemaglutinação , Espécies Introduzidas , Linfócitos/fisiologia , Masculino , Neutrófilos/fisiologia , Estresse Fisiológico/fisiologia , TemperaturaRESUMO
En diciembre de 2019 un nuevo coronavirus se identificó como causa de un brote de neumonía y distrés respiratorio en Wuhan, China. En marzo de 2020 fue declarado pandemia. Resulta importante conocer predictores de mala evolución para optimizar estrategias de cuidados. El índice neutrófilo-linfocito (INL) constituye un novedoso marcador pronóstico en enfermedades cardiovasculares, oncológicas e infecciosas. Este trabajo analiza su valor pronóstico en COVID-19. Se evaluó una cohorte retrospectiva de 131 pacientes con COVID-19 confirmado, entre marzo y mayo de 2020. Se analizaron las características basales de la población, la asociación del INL ≥ 3 con COVID-19 grave y la tasa de mortalidad de la enfermedad. La mediana de edad fue de 52 años, 54% fueron hombres. En 21 pacientes se encontraron criterios de gravedad, 9 de ellos requirieron ventilación mecánica. Presentó INL ≥ 3 el 81% (18/21) de los pacientes graves y el 33% (36/110) de los pacientes leves (OR = 8.74. IC del 95%: 2.74-27.86; p < 0.001). La edad y la hipertensión se asociaron con enfermedad grave. La mortalidad observada en la cohorte fue del 7% (9). En 7 de los 9 pacientes fallecidos se observó un INL ≥ 3 (p = 0.03). El INL, en conjunto con otros predictores, podría usarse como un marcador pronóstico temprano dada la alta accesibilidad y el bajo costo de la prueba.
In December 2019, a new coronavirus was identified as the cause of an outbreak of pneumonia and respiratory distress in Wuhan, China. It was declared pandemic in March 2020. It is important to know predictors of poor outcomes in order to optimize the strategies of care in newly diagnosed patients. The neutrophil to lymphocyte ratio (NLR) constitutes a novel prognostic marker for oncologic, cardiovascular and infectious diseases. We aimed to assess its prognostic value in COVID-19. We evaluated a retrospective cohort of 131 patients with COVID-19 from March to May 2020. We analyzed the association of an NLR ≥ 3 with severe COVID-19, baseline characteristics of the population and the mortality rate. The median age was 52 years, and 54% were men. 21 patients presented criteria of severe disease, 9 of them required mechanical ventilation. NLR ≥ 3 was found in 81% (18/21) of severe patients and in 33% (36/110) of mild patients (OR = 8.74. 95% CI 2.74-27.86; p < 0.001). Age and hypertension were associated with severe disease. A mortality rate of 7% (9) was obtained. Seven of the 9 patients who died presented NLR ≥ 3, with a significant association between mortality and NLR ≥ 3 (p = 0.03). NLR could be used in conjunction with other predictors, as an early prognostic marker in COVID-19 given its accessibility and low cost.