FERNANDA YAMAMOTO RICARDO DA SILVA
Projetos de Pesquisa
Unidades Organizacionais
Instituto do Coração, Hospital das Clínicas, Faculdade de Medicina
LIM/11 - Laboratório de Cirurgia Cardiovascular e Fisiopatologia da Circulação, Hospital das Clínicas, Faculdade de Medicina
LIM/11 - Laboratório de Cirurgia Cardiovascular e Fisiopatologia da Circulação, Hospital das Clínicas, Faculdade de Medicina
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- Comparison of acute kidney injury following brain death between male and female rats(2023) ARMSTRONG JR., Roberto; RICARDO-DA-SILVA, Fernanda Yamamoto; VIDAL-DOS-SANTOS, Marina; ANUNCIACAO, Lucas Ferreira da; OTTENS, Petra J.; CORREIA, Cristiano Jesus; MOREIRA, Luiz Felipe Pinho; LEUVENINK, Hendrik Gerrit Derk; BREITHAUPT-FALOPPA, Ana CristinaBackground: Clinical reports associate kidneys from female donors with worse prognostic in male recipients. Brain Death (BD) produces immunological and hemodynamic disorders that affect organ viability. Following BD, female rats are associated with increased renal inflammation interrelated with female sex hormone reduction. Here, the aim was to investigate the effects of sex on BD-induced Acute Kidney Injury (AKI) using an Isolated Perfused rat Kidney (IPK) model.Methods: Wistar rats, females, and males (8 weeks old), were maintained for 4h after BD. A left nephrectomy was performed and the kidney was preserved in a cold saline solution (30 min). IPK was performed under normothermic temperature (37 & DEG;C) for 90 min using WME as perfusion solution. AKI was assessed by morphological analyses, staining of complement system components and inflammatory cell markers, perfusion flow, and creatinine clearance. Results: BD-male kidneys had decreased perfusion flow on IPK, a phenomenon that was not observed in the kidneys of BD-females (p < 0.0001). BD-male kidneys presented greater proximal (p = 0.0311) and distal tubule (p = 0.0029) necrosis. However, BD-female kidneys presented higher expression of eNOS (p = 0.0060) and greater upregulation of inflammatory mediators, iNOS (p = 0.0051), and Caspase-3 (p = 0.0099). In addition, both sexes had increased complement system formation (C5b-9) (p=0.0005), glomerular edema (p = 0.0003), and nNOS (p = 0.0051).Conclusion: The present data revealed an important sex difference in renal perfusion in the IPK model, evidenced by a pronounced reduction in perfusate flow and low eNOS expression in the BD-male group. Nonetheless, the upregulation of genes related to the proinflammatory cascade suggests a progressive inflammatory process in BDfemale kidneys.
- Protective role of 17 beta-estradiol treatment in renal injury on female rats submitted to brain death(2021) ARMSTRONG-JR, Roberto; RICARDO-DA-SILVA, Fernanda Yamamoto; VIDAL-DOS-SANTOS, Marina; CORREIA, Cristiano de Jesus; ANUNCIACAO, Lucas Ferreira; SILVA, Raphael dos Santos Coutinho e; MOREIRA, Luiz Felipe Pinho; LEUVENINK, Henri Gerrit Derk; BREITHAUPT-FALOPPA, Ana CristinaBackground: Clinical and experimental data highlight the consequences of brain death on the quality of organs and demonstrate the importance of donor state to the results of transplantation. Female rats show higher cardio-pulmonary injury linked to decreased concentrations of female sex hormones after brain-dead (BD). This study evaluated the effect of 17 beta-estradiol on brain death induced renal injury in female rats. Methods: Female Wistar rats were randomically allocated into 4 groups: false-operation (Sham), BD, treatment with 17 beta-estradiol (50 mu g/mL, 2 mL/h) 3 h after brain death (E2-T3), or immediately after brain death confirmation (E2-T0). Creatinine, urea, cytokines, and complement system components were quantified. Renal injury markers, such as KIM-1, Caspase-3, BCL-2 and MMP2/9 were evaluated. Results: Brain death leads to increased kidney KIM-1 expression and longer 17 beta-estradiol treatment resulted in downregulation (P<0.0001). There was increase of neutrophil numbers in kidney from BD rats and E2 treatment was able to reduce it (P=0.018). Regarding complement elements, E2-T3 group evidenced E2 therapeutic effects, reducing C5b-9 (P=0.0004), C3aR (P=0.054) and C5aR (P=0.019). In parallel, there were 17 beta-estradiol effects in reducing MMP2 (P=0.0043), MMP9 (P=0.011), and IL-6 (P=0.024). Moreover, E2-T3 group improved renal function in comparison to BD group (P=0.0938). Conclusions: 17 beta-estradiol treatment was able to reduce acute kidney damage in BD female rats owing to its ability to prevent tissue damage, formation of C5b-9, and local synthesis of inflammatory mediators.
- Treatment with 17 beta-estradiol protects donor heart against brain death effects in female rat(2020) ARMSTRONG-JR, Roberto; RICARDO-DA-SILVA, Fernanda Yamamoto; CORREIA, Cristiano Jesus; VIDAL-DOS-SANTOS, Marina; ANUNCIACAO, Lucas Ferreira da; SILVA, Raphael Santos Coutinho e; MOREIRA, Luiz Felipe Pinho; LEUVENINK, Hendrik Gerrit Derk; BREITHAUPT-FALOPPA, Ana CristinaThe viability of donor organs is reduced by hemodynamic and immunologic alterations caused by brain death (BD). Female rats show higher heart inflammation associated with the reduction in female sex hormones after BD. This study investigated the effect of 17 beta-estradiol (E2) on BD-induced cardiac damage in female rats. Groups of female Wistar rats were assigned: Sham-operation (Sham), brain death (BD), treatment with E2 (50 mu g/ml, 2 ml/h) 3 h after BD (E2-T3), or immediately after BD confirmation (E2-T0). White blood cell (WBC) count was analyzed; cytokines and troponin-I were quantified. Heart histopathological changes and expression of endothelial nitric oxide synthase, endothelin-1, intercellular adhesion molecule-1, BCL-2, and caspase-3 were evaluated. Cardiac function was continuously assessed for 6 h by left ventricular pressure-volume loop analysis. E2 decreased the BD-induced median serum concentration of troponin-I (BD:864.2 vs. E2-T0:401.4;P = 0.009), increased BCL-2 (BD:0.086 vs. E2-T0:0.158; P = 0.0278) and eNOS median expression in the cardiac tissue (BD:0.001 vs. E2-T0:0.03 and E2-T3:0.0175; P < 0.0001), and decreased caspase-3 (BD:0.025 vs. E2-T0:0.006 and E2-T3:0.019; P = 0.006), WBC counts, leukocyte infiltration, and hemorrhage. 17 beta-estradiol treatment was effective in reducing cardiac tissue damage in brain-dead female rats owing to its ability to reduce leukocyte infiltration and prevent cardiomyocyte apoptosis.
- ESTRADIOL MODULATES LOCAL GUT INJURY INDUCED BY INTESTINAL ISCHEMIA-REPERFUSION IN MALE RATS(2017) RICARDO-DA-SILVA, Fernanda Yamamoto; FANTOZZI, Evelyn Thais; RODRIGUES-GARBIN, Sara; OLIVEIRA-FILHO, Ricardo Martins; VARGAFTIG, Bernardo Boris; BREITHAUPT-FALOPPA, Ana Cristina; LIMA, Wothan Tavares deIntestinal ischemia and reperfusion (I/R) triggers a systemic inflammatory response characterized by leukocyte mobilization from the bone marrow, release of cytokines to the circulation, and increased microvascular permeability, leading to high mortality. Females have shown attenuated inflammatory response to trauma when compared with males, indicatinga role for female sex hormones in this process. Here, we have evaluated the effect of estradiol on the local gut injury induced by I/R in male rats. I/R was induced by the clamping of the superior mesenteric artery for 45 min, followed by 2 h of reperfusion. Agroup received 17 beta-estradiol (280 mu g/kg, i.v., single dose) at 30 min of ischemia. Morphometric analysis of the gut showed I/R induced a reduction of villous height that was prevented by estradiol. White blood cells, notably granulocytes, were mobilized from the circulation to the intestine by I/R, which was also prevented by estradiol treatment. Groups had the intestine wrapped in a plastic bag to collect intestinal fluid, where leukocytescount, TNF-alpha, and IL-10 levels were increased by I/R. Serum chemokines (CINC-1, MIP-1 alpha, MIP-2), ICAM-1 expression in the mesenteric tissue, and neutrophils spontaneous migration measured in vitro were also increased after I/R. Estradiol treatment reduced leukocytes numbers and TNF-alpha on intestinal fluid, serum chemokine release and also downregulated MIP-1 alpha, MIP-2 gene expression, and spontaneous in vitro neutrophil migration. In conclusion, estradiol blunts intestinal injury induced by I/R by modulating chemokines release and leukocyte trafficking.
- Sex differences in the coagulation process and microvascular perfusion induced by brain death in rats(2020) CORREIA, Cristiano de Jesus; SILVA, Fernanda Yamamoto Ricardo da; ARMSTRONG, Roberto Junior; SANTOS, Marina Vidal dos; ANUNCIACAO, Lucas Ferreira da; SOBRAL, Marcelo Luiz Peixoto; SILVA, Raphael dos Santos Coutinho e; LEUVENINK, Hendrik Gerrit Derk; BREITHAUPT-FALOPPA, Ana Cristina; MOREIRA, Luiz Felipe PinhoBrain death (BD) leads to a systemic inflammation associated with the activation of coagulation, which could be related to decreased microcirculatory perfusion. Evidence shows that females exhibit higher platelet aggregability than males. Thus, we investigated sex differences in platelets, coagulation and microcirculatory compromise after BD. BD was induced in male and female (proestrus) Wistar rats. After 3 h, we evaluated: (i) intravital microscopy to evaluate mesenteric perfusion and leucocyte infiltration; (ii) platelet aggregation assay; (iii) rotational thromboelastometry; and (iv) SerumNOx-. Female rats maintained the mesenteric perfusion, whereas male reduced percentage of perfused vessels. Male BD presented higher platelet aggregation than the controls. In contrast, female BD had lower platelet aggregation than the control. Thromboelastometry indicated a reduction in clot firmness with increased clotting time in the female group compared with the male group. SerumNOx-level in female BD was higher than that in the male BD and female control. There is sex dimorphism in platelet function and clotting process, which are altered in different ways by BD. Thus, it is possible to connect the reduction in microcirculatory perfusion in males to intravascular microthrombi formation and the maintenance of perfusion in females to a higher inflammatory response and NO synthesis.
- 17 beta-Estradiol Treatment Protects Lungs Against Brain Death Effects in Female Rat Donor(2021) RICARDO-DA-SILVA, Fernanda Yamamoto; JR, Roberto Armstrong; VIDAL-DOS-SANTOS, Marina; CORREIA, Cristiano de Jesus; SILVA, Raphael dos Santos Coutinho e; ANUNCIACAO, Lucas Ferreira da; MOREIRA, Luiz Felipe Pinho; LEUVENINK, Hendrik Gerrit Derk; BREITHAUPT-FALOPPA, Ana CristinaBackground. Brain death (BD) affects the viability of lungs for transplantation. A correlation exists between high-lung inflammation after BD and the decrease in female sex hormones, especially estradiol. Therefore, we investigated the effects of 17 beta-estradiol (E2) treatment on the lungs of female brain dead rats. Methods. Female Wistar rats were divided into 4 groups: BD (submitted to BD for 6 h), sham (false operated), E2-T0 (treated with E2 immediately after BD; 50 mu g/mL, 2 mL/h), and E2-T3 (treated with E2 after 3 h of BD; 50 mu g/mL, 2 mL/h). Lung edema, hemorrhage, and leukocyte infiltration were analyzed. Adhesion molecules were evaluated, and analysis of NO synthase gene and protein expression was performed using real-time PCR and immunohistochemistry, respectively. Release of chemokines and matrix degradation in the lungs was analyzed. Results. BD increased leukocyte infiltration, as shown by intravital microscopy (P = 0.017), bronchoalveolar lavage cell count (P = 0.016), the release of inflammatory mediators (P = 0.02), and expression of adhesion molecules. BD also increased microvascular permeability and the expression and activity of matrix metalloproteinase-9 in the lungs. E2 treatment reduced leukocyte infiltration, especially in the E2-T3 group, release of inflammatory mediators, adhesion molecules, and matrix metalloproteinase activity in the lungs. Conclusions. E2 treatment was successful in controlling the lung inflammatory response in females submitted to BD. Our results suggest that E2 directly decreases the release of chemokines, restraining cell traffic into the lungs. Thus, E2 has a therapeutic potential, and its role in improving donor lung quality should be explored further.
- Acute lung injury induced by intestinal ischemia and reperfusion is altered in obese female mice(2018) FANTOZZI, Evelyn Thais; RODRIGUES-GARBIN, Sara; RICARDO-DA-SILVA, Fernanda Yamamoto; OLIVEIRA-FILHO, Ricardo Martins; SPINA, Domenico; TAVARES-DE-LIMA, Wothan; RIFFO-VASQUEZ, YaniraRational: Acute lung injury (ALI) is a common complication after intestinal ischemia and reperfusion (I/R) injury that can lead to acute respiratory distress syndrome (ARDS). We have previously demonstrated that females are protected against lung damage induced by intestinal I/R through an estrogen mediated mechanism. Objectives: To investigate the effect of obesity on ALI induced by intestinal I/R in female mice. Methods: C57B1/6 female mice were fed with a standard low-fat diet (SD) or a high-fat diet (HFD) for 9 weeks. Intestinal I/R injury was induced by a 45 min occlusion of the mesenteric artery followed by 2 and 24 h of reperfusion. Results: Significant increase in lung myeloperoxidase expression (MPO) and neutrophil numbers of SD and HFD mice occurred at 2 h and 24 h of reperfusion. Furthermore, HFD mice presented a significant increase in lung eosinophil peroxidase (EPO) expression and eosinophil numbers compared to SD mice. Lung wet/dry weight ratio was significantly greater in HFD mice at 2 and 24 h of reperfusion, accompanied by a significant increase in the expression of inducible NO in the lung tissue and a significant decrease in arterial oxygen saturation at 24 h of reperfusion relative to SD mice. Conclusion: Obesity predisposes female mice to increased pulmonary oedema and deterioration in gas exchange, which is accompanied by an increase in iNOS expression in the lung.