RAPHAEL DOS SANTOS COUTINHO E SILVA

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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

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Autor: RICARDO-DA-SILVA, Fernanda Yamamoto ×

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  • article 3 Citação(ões) na Scopus
    Long-term lung inflammation is reduced by estradiol treatment in brain dead female rats
    (2021) RICARDO-DA-SILVA, Fernanda Yamamoto; ARMSTRONG-JR, Roberto; VIDAL-DOS-SANTOS, Marina; CORREIA, Cristiano de Jesus; SILVA, Raphael dos Santos Coutinho e; ANUNCIACAO, Lucas Ferreira da; MOREIRA, Luiz Felipe Pinho; LEUVENINK, Henri Gerrit Derk; BREITHAUPT-FALOPPA, Ana Cristina
    OBJECTIVES: Lung transplantation is limited by the systemic repercussions of brain death (BD). Studies have shown the potential protective role of 17 beta-estradiol on the lungs. Here, we aimed to investigate the effect of estradiol on the long-lasting lung inflammatory state to understand a possible therapeutic application in lung donors with BD. METHODS: Female Wistar rats were separated into 3 groups: BD, subjected to brain death (6h); E2-T0, treated with 17 beta-estradiol (50 mu g/mL, 2 mL/h) immediately after brain death; and E2-T3, treated with 17 beta-estradiol (50 mu g/ml, 2 ml/h) after 3h of BD. Complement system activity and macrophage presence were analyzed. TNF-alpha, IL-1 beta, IL-10, and IL-6 gene expression (RT-PCR) and levels in 24h lung culture medium were quantified. Finally, analysis of caspase-3 gene and protein expression in the lung was performed. RESULTS: Estradiol reduced complement C3 protein and gene expression. The presence of lung macrophages was not modified by estradiol, but the release of inflammatory mediators was reduced and TNF-alpha and IL-1 beta gene expression were reduced in the E2-T3 group. In addition, caspase-3 protein expression was reduced by estradiol in the same group. CONCLUSIONS: Brain death-induced lung inflammation in females is modulated by estradiol treatment. Study data suggest that estradiol can control the inflammatory response by modulating the release of mediators after brain death in the long term. These results strengthen the idea of estradiol as a therapy for donor lungs and improving transplant outcomes.
  • article
    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 Cristina
    Background: 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.
  • article 4 Citação(ões) na Scopus
    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 Cristina
    The 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.
  • conferenceObject
    ESTRADIOL TREATMENT REDUCES LUNG LEUKOCYTE INFILTRATION AFTER BRAIN DEATH IN FEMALE RATS
    (2019) RICARDO-DA-SILVA, Fernanda Yamamoto; ARMSTRONG- JR., Roberto; VIDAL-DOS-SANTOS, Marina; SILVA, Raphael dos Santos Coutinho e; CORREIA, Cristiano de Jesus; MOREIRA, Luiz Felipe Pinho; LEUVENINK, Henri; BREITHAUPT-FALOPPA, Ana Cristina
  • article 3 Citação(ões) na Scopus
    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 Cristina
    Background. 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.
  • conferenceObject
    ESTRADIOL REDUCES HEART INJURY AND APOPTOSIS AFTER BRAIN DEATH IN FEMALE RATS
    (2019) JR, Roberto Armstrong; RICARDO-DA-SILVA, Fernanda Yamamoto; VIDAL-DOS-SANTOS, Marina; SILVA, Raphael dos Santos Coutinho e; CORREIA, Cristiano de Jesus; MOREIRA, Luiz Felipe Pinho; LEUVENINK, Henri Gerrit Derk; BREITHAUPT-FALOPPA, Ana Cristina
  • article 2 Citação(ões) na Scopus
    Hypertonic saline reduces cell infiltration into the lungs after brain death in rats
    (2020) CORREIA, Cristiano de Jesus; SILVA, Raphael dos Santos Coutinho e; SOARES, Rafaela Garcia Ferreira; JR, Roberto Armstrong; RICARDO-DA-SILVA, Fernanda Yamamoto; SANNOMIYA, Paulina; BREITHAUPT-FALOPPA, Ana Cristina; MOREIRA, Luiz Felipe P.
    Background: Lung transplantation is a treatment method for end stage lung disease, but the availability of donor lungs remains a major constraint. Brain death (BD) induces hemodynamic instability with microcirculatory hypoperfusion and increased inflammation, leading to pulmonary dysfunction. Hypertonic saline solution (HSS) is a volume expander possessing immunomodulatory effects. This study evaluated the influence of HSS on pulmonary dysfunction and inflammation in a rat model of BD. Methods: BD was induced by inflation of an intracranial balloon catheter. Rats were divided into [1]: Sham, without BD [2]; NS, NaCl treatment (0.9%, 4 mL/kg, i.v.) immediately after BD [3];HSS1, HSS treatment (NaCl 7.5%, 4 mL/kg, i.v.) immediately after BD; and [4] HSS60, HSS treatment 60 min post BD. All groups were analyzed after 360 min. Results: Animals subjected to BD exhibited increased exhaled O-2 and decreased CO2.The number of leukocytes in the lungs was significantly increased in the NS group (p = 0.002) and the HSS treatment was able to reduce it (p = 0.018 and HSS60 = 0.030). In parallel, HSS-treated rats showed reduced levels of ICAM-1 expression, which was increased in the NS compared to Sham group. Lung edema was found increased in the NS group animals compared to Sham and no effect of the HSS treatment was observed. There were no differences among the groups in terms of TNF-alpha, VEGF, and CINC-1 lung concentrations. Conclusions: HSS is capable of reducing inflammatory cell infiltration into the lung after BD induction, which is associated with the reduction of ICAM-1 expression in organ vessels.