PAULINA SANNOMIYA
Projetos de Pesquisa
Unidades Organizacionais
BMF, ICB - Docente
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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- HYPERTONIC SALINE SOLUTION REDUCES MESENTERIC MICROCIRCULATORY DYSFUNCTIONS AND BACTERIAL TRANSLOCATION IN A RAT MODEL OF STRANGULATED SMALL BOWEL OBSTRUCTION(2013) ZANONI, Fernando Luiz; CRUZ, Jose Walber Miranda Costa; MARTINS, Joilson Oliveira; BENABOU, Simon; GRECO, Karin Vicente; MORENO, Ana Carolina Ramos; MARTINEZ, Marina Baquerizo; CALDERARO, Franco Ferraro; SILVA, Mauricio Rocha e; SANNOMIYA, PaulinaWe examined the effects of hypertonic saline (HS) on inflammatory, metabolic variables, and bacterial translocation (BT) in rats submitted to intestinal obstruction and ischemia (IO). Male Wistar rats were submitted to IO and treated, 2 h thereafter, with lactated Ringer's (LR) (4 mL/kg per 5 min, i.v.) or HS (7.5% NaCl, 4 mL/kg per 5 min, i.v.). Twenty-four hours after IO, rats were also submitted to enterectomy/enteroanastomosis to resection of necrotized small bowel. Leukocyte-endothelial interactions were investigated by intravital microscopy and the expression of P-selectin and intercellular adhesion molecule 1 by immunohistochemistry. Bacterial cultures of mesenteric lymph nodes, liver, spleen, and blood were used to evaluate BT. Levels of chemokines (cytokine-induced neutrophil chemoattractants 1 and 2), insulin, and corticosterone were determined by enzyme-linked immunosorbent assay. Intestinal histology, serum urea and creatinine levels, and hepatic enzymes activities were performed to evaluate local and remote damage. Relative to IO and LR-treated rats, which exhibited increases in the number of rolling (1.5-fold), adhered (3.5-fold) and migrated (9.0-fold) leukocytes, and increased expression of P-selectin (3-fold) and intercellular adhesion molecule 1 (3-fold) on mesenteric microcirculation, treatment with HS followed by enterectomy reduced leukocyte-endothelial interactions and expression of both adhesion molecules to values attained in sham rats. Serum chemokines were normalized after treatment with both solutions followed by enterectomy. Hypertonic saline-treated rats demonstrated a significant reduction in BT to 50% in liver and spleen samples and bacteremia (14%), compared with 82% of BT in liver and spleen samples of IO and LR-treated rats and bacteremia (57%). Local intestinal damage was attenuated, and renal and hepatic function preserved by treatment with HS followed by enterectomy. Survival rate increased to 86% up to 15 days. Data presented suggest that HS solution followed by enterectomy reduces mesenteric microcirculatory dysfunctions and BT, attenuating local and remote damage in a model of strangulated small bowel obstruction.
- Effects of ethyl pyruvate on leukocyte-endothelial interactions in the mesenteric microcirculation during early sepsis treatment(2015) GUARDA, Ismael Francisco Mota Siqueira; CORREIA, Cristiano Jesus; BREITHAUPT-FALOPPA, Ana Cristina; FERREIRA, Sueli Gomes; MORENO, Ana Carolina Ramos; MARTINEZ, Marina Baquerizo; ROCHA-E-SILVA, Mauricio; SANNOMIYA, PaulinaOBJECTIVES: Experimental studies on sepsis have demonstrated that ethyl pyruvate is endowed with antioxidant and anti-inflammatory properties. This study aimed to investigate the effects of ethyl pyruvate on leukocyteendothelial interactions in the mesenteric microcirculation in a live Escherichia coli-induced sepsis model in rats. METHODS: Male Wistar rats were administered an intravenous suspension of E. coli bacteria or were subjected to a sham procedure. Three hours after bacterial infusion, the rats were randomized into the following groups: a control group without treatment, a group treated with lactated Ringer's solution (4 mL/kg, i.v.), and a group treated with lactated Ringer's solution (4 mL/kg, i.v.) plus ethyl pyruvate (50 mg/kg). At 24 h after bacterial infusion, leukocyte-endothelial interactions were investigated using intravital microscopy, and the expression of P-selectin and intercellular adhesion molecule-1 was evaluated via immunohistochemistry. White blood cell and platelet counts were also determined at baseline and 3 h and 24 h after E. coli inoculation. RESULTS: The non-treated and lactated Ringer's solution-treated groups exhibited increases in the numbers of rolling leukocytes (similar to 2.5-fold increase), adherent cells (similar to 3.0-fold), and migrated cells (similar to 3.5-fold) compared with the sham group. In contrast, treatment with Ringer's ethyl pyruvate solution reduced the numbers of rolling, adherent and migrated leukocytes to the levels observed in the sham group. Additionally, the expression of P-selectin and intercellular adhesion molecule-1 was significantly increased on mesenteric microvessels in the non-treated group compared with the sham group (p<0.001). The expression of both adhesion molecules was reduced in the other groups, with ethyl pyruvate being more effective than lactated Ringer's solution. Infusion of bacteria caused significant leukopenia (3 h), followed by leukocytosis with granulocytosis (24 h). There was also an intense and progressive reduction in the number of platelets. However, no differences were observed after treatment with the different solutions. CONCLUSIONS: The presented data suggest that ethyl pyruvate efficiently reduces the inflammatory response in the mesenteric microcirculation in an experimental model of sepsis induced by live E. coli and is associated, at least in part, with down-regulation of P-selectin and intercellular adhesion molecule-1.
- Inhibition of Autonomic Storm by Epidural Anesthesia Does Not Influence Cardiac Inflammatory Response After Brain Death in Rats(2012) SILVA, I. A.; CORREIA, C. J.; SIMAS, R.; CORREIA, C. D. J.; CRUZ, J. W. M. C.; FERREIRA, S. G.; ZANONI, F. L.; MENEGAT, L.; SANNOMIYA, P.; MOREIRA, L. F. P.Background. After brain death (BD) donors usually experience cardiac dysfunction, which is responsible for a considerable number of unused organs. Causes of this cardiac dysfunction are not fully understood. Some authors argue that autonomic storm with severe hemodynamic instability leads to inflammatory activation and myocardial dysfunction. Objectives. To investigate the hypothesis that thoracic epidural anesthesia blocks autonomic storm and improves graft condition by reducing the inflammatory response. Methods. Twenty-eight male Wistar rats (250-350 g) allocated to four groups received saline or bupivacaine via an epidural catheter at various times in relation to brain-death induction. Brain death was induced by a sudden increase in intracranial pressure by rapid inflation of a ballon catheter in the extradural space. Blood gases, electrolytes, and lactate analyses were performed at time zero, and 3 and 6 hours. Blood leukocytes were counted at 0 and 6 hours. After 6 hours of BD, we performed euthanasia to measure vascular adhesion molecule (VCAM)-1, intracellular adhesion molecule (ICAM)-1, interleukin (IL)-1 beta, tumor necrosis factor (TNF)-alpha, Bcl-2 and caspase-3 on cardiac tissue. Results. Thoracic epidural anesthesia was effective to block the autonomic storm with a significant difference in mean arterial pressure between the untreated (saline) and the bupivacaine group before BD (P < .05). However, no significant difference was observed for the expressions of VCAM-1, ICAM-1, TNF-alpha, IL-1 beta, Bcl-2, and caspase-3 (P > .05). Conclusion. Autonomic storm did not seem to be responsible for the inflammatory changes associated with BD; thoracic epidural anesthesia did not modify the expression of inflammatory mediators although it effectively blocked the autonomic storm.
- 17 beta-Estradiol protects against lung injuries after brain death in male rats(2018) VIEIRA, Roberta Figueiredo; BREITHAUPT-FALOPPA, Ana Cristina; MATSUBARA, Bruno Carvalho; RODRIGUES, Geovana; SANCHES, Marcelo Petrof; ARMSTRONG- JR., Roberto; FERREIRA, Sueli Gomes; CORREIA, Cristiano de Jesus; MOREIRA, Luiz Felipe P.; SANNOMIYA, PaulinaBACKGROUND: Brain death elicits microvascular dysfunction and inflammation, and thereby compromises lung viability for transplantation. As 17 beta-estradiol was shown to be anti-inflammatory and vascular protective, we investigated its effects on lung injury after brain death in male rats. METHODS: Wistar rats were assigned to: sham-operation by trepanation only (SH, n = 7); brain death (BD, n = 7); administration of 17-estradiol (280 tg/kg, iv) at 60 minutes after brain death (BD-E2, n = 7). Experiments were performed 180 minutes thereafter. Histopathological changes in the lung were evaluated by histomorphometry. Gene expression of inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), and endothelin-1 was measured by real-time polymerise chain reaction. Protein expression of NO synthases, endothelin-1, platelet endothelial cell adhesion molecule-1 (PECAM-1), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), BCL-2, and caspase 3 was assessed by immunohistochemistry. Cytokines were quantified by enzyme linked immunosorbent assay. RESULTS: Treatment with 17P-estradiol after brain death decreased lung edema and hemorrhage (p < 0.0001), and serum levels of cytokine-induced neutrophil chemoattractant-1 (CINC-1; p = 0.0020). iNOS (p < 0.0001) and VCAM-1 (p < 0.0001) also diminished at protein levels, while eNOS accumulated (p = 0.0002). However, gene expression of iNOS, eNOS, and endothelin-1 was comparable among groups, as was protein expression of endothelin-1, ICAM-1, BCL-2, and caspase 3. CONCLUSIONS: 17P-Estradiol effectively reduces lung injury in brain-dead rats mainly due to its ability to regulate NO synthases. Thus, the drug may improve lung viability for transplantation. J Heart Lung Transplant 2018;37:1381-1387 (C) 2018 International Society for Heart and Lung Transplantation. All rights reserved.
- Differential Effects of Brain Death on Rat Microcirculation and Intestinal Inflammation: Female Versus Male(2018) FERREIRA, Sueli Gomes; ARMSTRONG- JR., Roberto; KUDO, Guilherme Konishi; CORREIA, Cristiano de Jesus; REIS, Sabrina Thalita dos; SANNOMIYA, Paulina; BREITHAUPT-FALOPPA, Ana Cristina; MOREIRA, Luiz Felipe PinhoBrain death (BD) affects organs by multiple mechanisms related to hemodynamic effects, hormonal changes, and the systemic inflammatory response, which reduce organ function and viability. BD reduces microcirculatory perfusion in rat mesentery; this disturbance is also observed in the pancreas and lungs. Sex hormones can affect microcirculatory function, altering tissue perfusion and influencing the inflammatory process. Here, we present differences between sexes in the microcirculatory alterations generated by BD and in inflammatory infiltrate. Male, female, and ovariectomized-female Wistar rats were submitted to BD by intracranial balloon catheter sudden inflation. BD was confirmed by maximally dilated and fixed pupils, apnea, absence of reflexes, and a drop in mean arterial pressure. Perfusion and flow of the mesenteric microcirculation were analyzed. Intestinal myeloperoxidase activity and leukocyte infiltration were quantified. ELISA quantified serum estradiol, corticosterone, and inflammatory mediators, whereas expression of eNOS, endothelin, and endothelial adhesion molecule was measured by immunohistochemistry. Male rats presented lower percentages of mesenteric perfused microvessels and reduced blood flow compared to females. The female group presented higher eNOS and endothelin expression. Leukocyte infiltration into intestinal walls was higher in females in comparison to that in males. Moreover, the female group showed higher mesenteric vessel ICAM-1 expression than males, whereas serum TNF-alpha, IL-1 beta, and IL-10 levels did not differ between sexes. The high estradiol concentration before BD and high eNOS expression apparently favored the maintenance of microvascular perfusion/flow; however, BD caused an acute reduction of female sex hormone concentration and higher ICAM-1 level; thus, the proinflammatory organ status after BD is favored.
- 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.
- HYPERTONIC SALINE SOLUTION REDUCES MICROCIRCULATORY DYSFUNCTION AND INFLAMMATION IN A RAT MODEL OF BRAIN DEATH(2019) CORREIA, Cristiano de Jesus; ARMSTRONG JR., Roberto; CARVALHO, Priscila Oliveira de; SIMAS, Rafael; SANCHEZ, Daniela Crisina Janolli; BREITHAUPT-FALOPPA, Ana Cristina; SANNOMIYA, Paulina; MOREIRA, Luiz Felipe PinhoBackground: Brain death (BD) induces hemodynamic instability with microcirculatory hypoperfusion, leading to increased organ inflammation and dysfunction. This study investigated the effects of 7.5% hypertonic saline solution (HSS) on mesenteric microcirculatory dysfunction and inflammation in a rat model of BD. Methods: Male Wistar rats were anesthetized and mechanically ventilated. BD was induced by rapidly inflating an intracranial balloon catheter. The rats were randomly divided into: SH, sham-operated rats subjected to trepanation; NS, rats treated with NaCl 0.9%, 4 mL/kg immediately after BD; T-1, rats treated with HSS (NaCl 7.5%, 4 mL/kg) immediately or 60 min after BD, T-60. All groups were analyzed 180 min after the start of the experiment. Results: Rats in BD groups presented with a similar hypertensive peak, followed by hypotension. Proportion of perfused small vessels was decreased in the NS group (46%) compared with the SH group (74%, P = 0.0039). HSS restored the proportion of perfused vessels (T-1 = 71%, P = 0.0018). The anti-endothelial nitric oxide synthase (eNOS) protein expression significantly increased in rats given HSS (T-1, and T-60, P = 0.0002). Similar results were observed regarding endothelin-1 (P<0.0001). Increased numbers of rolling (P = 0.0015) and migrated (P = 0.0063) leukocytes were observed in the NS group compared with the SH group. Rats given HSS demonstrated an overall reduction in leukocyte-endothelial interactions. The ICAM-1 levels increased in the NS group compared with the SH group, and decreased in the HSS-treated groups (P = 0.0002). Conclusions: HSS may improve the density of mesenteric perfused small vessels due to its effects on eNOS and endothelin-1 protein expression, and reduces inflammation by decreasing leukocyte adhesion and migration in a rat model of BD.
- 17 beta-Estradiol prevents mesenteric injury induced by occlusion of the proximal descending aorta in male rats(2018) SOUSA, Paulo Thales Rocha de; BREITHAUPT-FALOPPA, Ana Cristina; CORREIA, Cristiano de Jesus; SIMAO, Raif Restivo; FERREIRA, Sueli Gomes; FIORELLI, Alfredo Inacio; MOREIRA, Luiz Felipe Pinho; SANNOMIYA, PaulinaObjective: In surgical aortic repair or cardiac surgery with aorta occlusion, the occurrence of mesenteric ischemia and bowel injury has been associated with higher short-term mortality. The vascular protection of estrogens has been investigated and is mainly mediated by increasing the availability of nitric oxide (NO). Therefore, this study investigated the role of 17 beta-estradiol on visceral ischemia-reperfusion (I/R) injury after descending aorta occlusion in male rats. Methods: Mesenteric ischemia was induced in male Wistar rats by placing a 2F Fogarty arterial embolectomy catheter (Edwards Lifesciences, Irvine, Calif) in the descending aorta, which remained occluded for 15 minutes, followed by reperfusion for up to 2 hours. Rats were divided into four groups: (1) rats that underwent surgical manipulation only (sham, n = 22); (2) rats that underwent I/R injury (n = 22); (3) rats treated with intravenous 17b-estradiol (280 mu g/kg) 30 minutes before I/R (n = 22); (4) or at the beginning of reperfusion (n = 22). Intestinal histopathologic changes were evaluated by histomorphometry. Mesenteric microcirculatory alterations were assessed by laser Doppler flowmetry and intravital microscopy technique. Protein expression of intercellular adhesion molecule-1, P-selectin, endothelial NO synthase (eNOS), and endothelin-1 was evaluated by immunohistochemistry; in addition, eNOS and endothelin-1 gene expressions were quantified by real-time polymerase chain reaction. Serum cytokines were measured by enzyme-linked immunosorbent assay. Results: Relative to the sham group, the I/R group exhibited a highly pronounced loss of intestine mucosal thickness, a reduction in mesenteric blood flow (P=.0203), increased migrated leukocytes (P <.05), and high mortality rate (35%). Treatment with 17 beta-estradiol before aorta occlusion preserved intestine mucosal thickness (P <1/4>.0437) and mesenteric blood flow (P=.0251), reduced the number of migrated leukocytes (P <.05), and prevented any fatal occurrence. Furthermore, 17 beta-estradiol downregulated the expression of intercellular adhesion molecule-1 (P=.0001) and P-selectin (P <.0001) on the endothelium and increased the protein expression of eNOS (P <.0001). The gene expressions of eNOS and endothelin-1 did not differ between the groups. Conclusions: The prophylactic treatment with 17 beta-estradiol showed better overall repercussions and was able to prevent any fatal occurrence, increase eNOS expression, thus preserving mesenteric perfusion and intestinal integrity, and reduce inflammation. Clinical Relevance: The results of this study show that 17b-estradiol might be a supplementary approach to prevent mesenteric ischemia and intestinal bowel injury caused by major surgical procedures, particularly when aortic clamping is involved.