Fcγ RIIb protects from reperfusion injury by controlling antibody and type I IFN-mediated tissue injury and death.

Intestinal ischemia and reperfusion (I/R) is accompanied by an exacerbated inflammatory response characterized by deposition of IgG, release of inflammatory mediators, and intense neutrophil influx in the small intestine, resulting in severe tissue injury and death. We hypothesized that Fcγ RIIb activation by deposited IgG could inhibit tissue damage during I/R. Our results showed that I/R induction led to the deposition of IgG in intestinal tissue during the reperfusion phase. Death upon I/R occurred earlier and was more frequent in Fcγ RIIb-/- than WT mice. The higher lethality rate was associated with greater tissue injury and bacterial translocation to other organs. Fcγ RIIb-/- mice presented changes in the amount and repertoire of circulating IgG, leading to increased IgG deposition in intestinal tissue upon reperfusion in these mice. Depletion of intestinal microbiota prevented antibody deposition and tissue damage in Fcγ RIIb-/- mice submitted to I/R. We also observed increased production of ROS on neutrophils harvested from the intestines of Fcγ RIIb-/- mice submitted to I/R. In contrast, Fcγ RIII-/- mice presented reduced tissue damage and neutrophil influx after reperfusion injury, a phenotype reversed by Fcγ RIIb blockade. In addition, we observed reduced IFN-ß expression in the intestines of Fcγ RIII-/- mice after I/R, a phenotype that was also reverted by blocking Fcγ RIIb. IFNAR-/- mice submitted to I/R presented reduced lethality and TNF release. Altogether our results demonstrate that antibody deposition triggers Fcγ RIIb to control IFN-ß and IFNAR activation and subsequent TNF release, tailoring tissue damage, and death induced by reperfusion injury.

Melatonin prevents hyperglycemia in a model of sleep apnea.

OBJECTIVE: Obstructive sleep apnea is a common disorder associated with aging and obesity. Apneas cause repeated arousals, intermittent hypoxia, and oxidative stress. Changes in glucolipidic profile occur in apnea patients, independently of obesity. Animal models of sleep apnea induce hyperglycemia. This study aims to evaluate the effect of the antioxidants melatonin and N-acetylcysteine on glucose, triglyceride, and cholesterol levels in animals exposed to intermittent hypoxia. MATERIALS AND METHODS: Two groups of Balb/c mice were exposed to intermittent hypoxia (n = 36) or sham intermittent hypoxia (n = 36) for 35 days. The intermittent hypoxia group underwent a total of 480 cycles of 30 seconds reducing the inspired oxygen fraction from 21% to 7 ± 1% followed by 30 seconds of normoxia, during 8 hours daily. Melatonin or N-acetylcysteine were injected intraperitonially daily from day 21 on. RESULTS: At day 35, glucose levels were significantly higher in the intermittent hypoxia group than in the control group. The intermittent hypoxia groups receiving N-acetylcysteine and vehicle showed higher glucose levels than the group receiving melatonin. The lipid profile was not affected by intermittent hypoxia or antioxidant administration. CONCLUSIONS: The present results suggest that melatonin prevents the well-recognized increase in glucose levels that usually follows exposure to intermittent hypoxia. Further exploration of the role of melatonin in sleep apnea is warranted.

Uncoupling protein-2 mRNA expression in mice subjected to intermittent hypoxia.

OBJECTIVE: To investigate the effect of intermittent hypoxia-a model of obstructive sleep apnea (OSA)-on pancreatic expression of uncoupling protein-2 (UCP2), as well as on glycemic and lipid profiles, in C57BL mice. METHODS: For 8 h/day over a 35-day period, male C57BL mice were exposed to intermittent hypoxia (hypoxia group) or to a sham procedure (normoxia group). The intermittent hypoxia condition involved exposing mice to an atmosphere of 92% N and 8% CO2 for 30 s, progressively reducing the fraction of inspired oxygen to 8 ± 1%, after which they were exposed to room air for 30 s and the cycle was repeated (480 cycles over the 8-h experimental period). Pancreases were dissected to isolate the islets. Real-time PCR was performed with TaqMan assays. RESULTS: Expression of UCP2 mRNA in pancreatic islets was 20% higher in the normoxia group than in the hypoxia group (p = 0.11). Fasting serum insulin was higher in the hypoxia group than in the normoxia group (p = 0.01). The homeostasis model assessment of insulin resistance indicated that, in comparison with the control mice, the mice exposed to intermittent hypoxia showed 15% lower insulin resistance (p = 0.09) and 21% higher pancreatic ß-cell function (p = 0.01). Immunohistochemical staining of the islets showed no significant differences between the two groups in terms of the area or intensity of α- and ß-cell staining for insulin and glucagon. CONCLUSIONS: To our knowledge, this is the first report of the effect of intermittent hypoxia on UCP2 expression. Our findings suggest that UCP2 regulates insulin production in OSA. Further study of the role that UCP2 plays in the glycemic control of OSA patients is warranted.

Uncoupling protein-2 mRNA expression in mice subjected to intermittent hypoxia / Expressão do mRNA da uncoupling protein-2 em camundongos submetidos à hipóxia intermitente

Objective: To investigate the effect of intermittent hypoxia-a model of obstructive sleep apnea (OSA)-on pancreatic expression of uncoupling protein-2 (UCP2), as well as on glycemic and lipid profiles, in C57BL mice. Methods: For 8 h/day over a 35-day period, male C57BL mice were exposed to intermittent hypoxia (hypoxia group) or to a sham procedure (normoxia group). The intermittent hypoxia condition involved exposing mice to an atmosphere of 92% N and 8% CO2 for 30 s, progressively reducing the fraction of inspired oxygen to 8 ± 1%, after which they were exposed to room air for 30 s and the cycle was repeated (480 cycles over the 8-h experimental period). Pancreases were dissected to isolate the islets. Real-time PCR was performed with TaqMan assays. Results: Expression of UCP2 mRNA in pancreatic islets was 20% higher in the normoxia group than in the hypoxia group (p = 0.11). Fasting serum insulin was higher in the hypoxia group than in the normoxia group (p = 0.01). The homeostasis model assessment of insulin resistance indicated that, in comparison with the control mice, the mice exposed to intermittent hypoxia showed 15% lower insulin resistance (p = 0.09) and 21% higher pancreatic β-cell function (p = 0.01). Immunohistochemical staining of the islets showed no significant differences between the two groups in terms of the area or intensity of α- and β-cell staining for insulin and glucagon. Conclusions: To our knowledge, this is the first report of the effect of intermittent hypoxia on UCP2 expression. Our findings suggest that UCP2 regulates insulin production in OSA. Further study of the role that UCP2 plays in the glycemic control of OSA patients is warranted. .

Objetivo: Investigar o efeito da hipóxia intermitente com um modelo de apneia obstrutiva do sono (AOS) sobre a expressão de uncoupling protein-2 (UCP2), assim como sobre perfis glicêmicos e lipídicos, em camundongos C57BL. Métodos: Camundongos C57BL machos foram expostos a hipóxia intermitente ou hipóxia simulada (grupo controle) 8 h/dia durante 35 dias. A condição de hipóxia intermitente envolveu a exposição dos camundongos a uma atmosfera de 92% de N e 8% de CO2 por 30 s, com redução progressiva de fração de O2 inspirado até 8 ± 1%, seguida por exposição a ar ambiente por 30 s e repetições do ciclo (480 ciclos no período experimental de 8 h). Os pâncreas foram dissecados para isolar as ilhotas. Foi realizada PCR em tempo real utilizando o método TaqMan. Resultados: A expressão do mRNA da UCP2 nas ilhotas pancreáticas foi 20% maior no grupo controle que no grupo hipóxia (p = 0,11). A insulina sérica de jejum foi maior no grupo hipóxia do que no grupo controle (p = 0,01). O modelo de avaliação da homeostase de resistência à insulina indicou que, em comparação com os camundongos controle, aqueles expostos à hipóxia intermitente apresentaram 15% menor resistência à insulina (p = 0,09) e 21% maior função das células beta (p = 0,01). A coloração das ilhotas pancreáticas por imuno-histoquímica não mostrou diferenças significativas entre os grupos em termos da área ou da intensidade das células alfa e beta, marcadas por insulina e glucagon. Conclusões: Segundo nosso conhecimento, esta é a primeira descrição do efeito da hipóxia intermitente sobre a expressão da UCP2. Nossos achados sugerem que UCP2 regula a produção de insulina na AOS. Futuras investigações sobre o papel da UCP2 no controle glicêmico em pacientes com AOS são justificadas. .

Melatonin prevents hyperglycemia in a model of sleep apnea

Objective Obstructive sleep apnea is a common disorder associated with aging and obesity. Apneas cause repeated arousals, intermittent hypoxia, and oxidative stress. Changes in glucolipidic profile occur in apnea patients, independently of obesity. Animal models of sleep apnea induce hyperglycemia. This study aims to evaluate the effect of the antioxidants melatonin and N-acetylcysteine on glucose, triglyceride, and cholesterol levels in animals exposed to intermittent hypoxia. Materials and methods Two groups of Balb/c mice were exposed to intermittent hypoxia (n = 36) or sham intermittent hypoxia (n = 36) for 35 days. The intermittent hypoxia group underwent a total of 480 cycles of 30 seconds reducing the inspired oxygen fraction from 21% to 7 ± 1% followed by 30 seconds of normoxia, during 8 hours daily. Melatonin or N-acetylcysteine were injected intraperitonially daily from day 21 on. Results At day 35, glucose levels were significantly higher in the intermittent hypoxia group than in the control group. The intermittent hypoxia groups receiving N-acetylcysteine and vehicle showed higher glucose levels than the group receiving melatonin. The lipid profile was not affected by intermittent hypoxia or antioxidant administration. Conclusions The present results suggest that melatonin prevents the well-recognized increase in glucose levels that usually follows exposure to intermittent hypoxia. Further exploration of the role of melatonin in sleep apnea is warranted. Arch Endocrinol Metab. 2015;59(1):66-70 .

Ecocardiografia em pacientes com apneia do sono grave com e sem pressão arterial controlada: estudo transversal / Echocardiography in patients with severe sleep apnea with and without controlled blood pressure: cross sectional study

A apneia obstrutiva do sono (AOS) afeta a anatomia e função do coração. Ocorre hipertensão arterial em metade dos casos de AOS, dificultando atribuir a etiologia dessas alterações separadamente à hipertensão arterial ou à apneia do sono. Métodos: Estudo transversal de pacientes com índice de apneia-hipopneia maior que 50 eventos por hora. As variáveis ecocardiográficas comparadas em indivíduos com hipertensão arterial controlada e não controlada foram: 1) fração de ejeção, 2) diâmetro da aorta, 3) diâmetro do átrio esquerdo, 4) diâmetro de ventrículo direito, 5) diâmetros do ventrículo esquerdo diastólico e sistólico, 6) percentagem delta, 7) espessura do septo, 8) espessura da parede posterior. Resultados: Foram incluídos 83 voluntários, 50 com pressão arterial não controlada. Em média, a idade era 47 ± 9,5 anos, o índice de massa corporal 34 ± 5,4 Kg/m2 , o índice de apneia-hipopneia 86 ± 18 eventos/hora. Sessenta pacientes apresentaram anormalidade no ecocardiograma. A hipertrofia de ventrículo esquerdo foi o achado mais comum, sem diferença de frequência em controles (39%) e em hipertensos (48%), seguida por disfunção diastólica em controles (27%) e em hipertensos (32%). Conclusões: Indivíduos com apneia do sono grave e pressão arterial controlada apresentam alterações no ecocardiograma de tipo e frequência semelhantes aos com hipertensão não controlada. Isso sugere que a apneia do sono pode causar dano cardíaco independentemente de hipertensão. Quando não explicáveis por hipertensão arterial, achados como hipertrofia de ventrículo esquerdo podem ser provocados por apneia do sono...

Obstructive sleep apnea (OSA) affects the cardiac anatomy and function. Hypertension occurs in half the OSA cases, making it difficult to attribute the cause of these changes separately to arterial hypertension or sleep apnea. Methods: Prospective cross-sectional study of volunteers with apnea-hypopnea index >50 events per hour. The echocardiographic variables were analyzed: 1) ejection fraction, 2) aortic diameter, 3) left atrial diameter, 4) right ventricular diameter, 5) diastolic and systolic diameters of the left ventricle, 6) delta percentage, 7) septum thickness, 8) posterior wall thickness. Results: There were 83 participants, 74 men, 50 with hypertension. The average age was 47 ± 9.5 years, body mass index of 34 ± 5.4 kg/m2 , apnea-hypopnea index of 86±18 events/hour, and minimum oxygen saturation of 55 ± 17%. Left ventricular hypertrophy was the most common echocardiographic abnormality in subjects without hypertension (39%) and with hypertension (48%), followed by diastolic dysfunction in subjects with normal blood pressure (27%) and with high blood pressure (32%). There was no statistically significant difference in echocardiographic characteristics between hypertensive subjects with those with normal pressure. Conclusions: Individuals with normal blood pressure and severe sleep apnea show abnormalities in the echocardiogram with frequency similar to that observed in patients with high blood pressure. This suggests that sleep apnea can cause ventricular overload independently of hypertension. When not explained by high blood pressure, left ventricular hypertrophy can be caused by sleep apnea...