RAPHAEL DOS SANTOS COUTINHO E 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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- 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 CristinaOBJECTIVES: 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.
- Perspectives of bilateral thoracic sympathectomy for treatment of heart failure(2021) SILVA, Raphael dos Santos Coutinho E; ZANONI, Fernando Luiz; SIMAS, Rafael; MOREIRA, Luiz Felipe PinhoSurgical neuromodulation therapies are still considered a last resort when standard therapies have failed for patients with progressive heart failure (HF). Although a number of experimental studies have provided robust evidence of its effectiveness, the lack of strong clinical evidence discourages practitioners. Thoracic unilateral sympathectomy has been extensively studied and has failed to show significant clinical improvement in HF patients. Most recently, bilateral sympathectomy effect was associated with a high degree of success in HF models, opening the perspective to be investigated in randomized controlled clinical trials. In addition, a series of clinical trials showed that bilateral sympathectomy was associated with a decreased risk of sudden death, which is an important outcome in patients with HF. These aspects indicates that bilateral sympathectomy could be an important alternative in the treatment of HF wherein pharmacological treatment barely reaches the target dose.
- 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.
- 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.