FRANCISCO GARCIA SORIANO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
LIM/51 - Laboratório de Emergências Clínicas, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/51 - Laboratório de Emergências Clínicas, Hospital das Clínicas, Faculdade de Medicina - Líder
46 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 46
- Gastrin-Releasing Peptide Receptor Antagonism Induces Protection from Lethal Sepsis: Involvement of Toll-like Receptor 4 Signaling(2012) PETRONILHO, Fabricia; VUOLO, Francieli; GALANT, Leticia Selinger; CONSTANTINO, Larissa; TOMASI, Cristiane Damiani; GIOMBELLI, Vinicius Renne; SOUZA, Cldudio Teodoro de; SILVA, Sabrina da; BARBEIRO, Denise Frediani; SORIANO, Francisco Garcia; STRECK, Emilio Luiz; RITTER, Cristiane; ZANOTTO-FILHO, Alfeu; PASQUALI, Matheus Augusto; GELAIN, Daniel Pens; RYBARCZYK-FILHO, Jose Luiz; MOREIRA, Jose Claudio Fonseca; BLOCK, Norman L.; ROESLER, Rafael; SCHWARTSMANN, Gilberto; SCHALLY, Andrew V.; DAL-PIZZOL, FelipeIn sepsis, toll-like receptor (TLR)-4 modulates the migration of neutrophils to infectious foci, favoring bacteremia and mortality. In experimental sepsis, organ dysfunction and cytokines released by activated macrophages can be reduced by gastrin-releasing peptide (GRP) receptor (GRPR) antagonist RC-3095. Here we report a link between GRPR and TLR-4 in experimental models and in sepsis patients. RAW 264.7 culture cells were exposed to lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-alpha and RC-3095 (10 ng/mL), Male Wistar rats were subjected to cecal ligation and puncture (CLP), and RC-3095 was administered (3 mg/kg, subcutaneously); after 6 h, we removed the blood, bronchoalveolar lavage, peritoneal lavage and lung. Human patients with a clinical diagnosis of sepsis received a continuous infusion with RC-3095 (3 mg/kg, intravenous) over a period of 12 h, and plasma was collected before and after RC-3095 administration and, in a different set of patients with systemic inflammatory response syndrome (SIRS) or sepsis. GRP plasma levels were determined. RC-3095 inhibited TLR-4, extracellular-signal-related kinase (ERK)-1/2, Jun NH2-terminal kinase (JNK) and Akt and decreased activation of activator protein 1 (AP-1), nuclear factor (NF)-kappa B and interleukin (IL)-6 in macrophages stimulated by LPS. It also decreased IL-6 release from macrophages stimulated by TNF-alpha. RC-3095 treatment in CLP rats decreased lung TLR-4, reduced the migration of cells to the lung and reduced systemic cytokines and bacterial dissemination. Patients with sepsis and systemic inflammatory response syndrome have elevated plasma levels of GRP which associates with clinical outcome in the sepsis patients. These findings highlight the role of GRPR signaling in sepsis outcome and the beneficial action of GRPR antagonists in controlling the inflammatory response in sepsis through a mechanism involving at least inhibition of TLR-4 signaling. Online address: http://www.molmed.org doi: 10.2119/molmed.2012.00083
- The contributions of dipeptidyl peptidase IV to inflammation in heart failure(2016) SALLES, Thiago de Almeida; ZOGBI, Camila; LIMA, Thais Martins de; CARNEIRO, Camila de Godoi; GARCEZ, Alexandre Teles; BARBEIRO, Hermes Vieira; ANTONIO, Ednei Luiz; SANTOS, Leonardo dos; PEREIRA, Alexandre da Costa; TUCCI, Paulo Jose Ferreira; FARIA, Daniele de Paula; SORIANO, Francisco Garcia; GIRARDI, Adriana Castello CostaCirculating dipeptidyl peptidase IV (DPPIV) activity correlates with cardiac dysfunction in humans and experimental heart failure (HF) models. Similarly, inflammatory markers are associated with poorer outcomes in HF patients. However, the contributions of DPPIV to inflammation in HF remain elusive. Therefore, this study aimed to investigate whether the cardioprotective effects of DPPIV inhibition after myocardial injury are accompanied by reduced cardiac inflammation, whether circulating DPPIV activity correlates with the levels of systemic inflammatory markers in HF patients, and whether leukocytes and/or splenocytes may be one of the sources of circulating DPPIV in HF. Experimental HF was induced in male Wistar rats by left ventricular myocardial injury after radiofrequency catheter ablation. The rats were divided into three groups: sham, HF, and HF + DPPIV inhibitor (sitagliptin). Six weeks after surgery, cardiac function, perfusion and inflammatory status were evaluated. Sitagliptin treatment improved cardiac function and perfusion, reduced macrophage infiltration, and diminished the levels of inflammatory biomarkers including TNF-alpha, IL-1 beta, and CCL2. In HF patients, serum DPPIV activity correlated with CCL2, suggesting that leukocytes may be the source of circulating DPPIV in HF. Unexpectedly, DPPIV release was higher in splenocytes from HF rats and similar in HF circulating mononuclear cells compared with those from sham, suggesting an organ-specific modulation of DPPIV in HF. Collectively, our data provide new evidence that the cardioprotective effects of DPPIV inhibition in HF may be due to suppression of inflammatory cytokines. Moreover, they suggest that a vicious circle between DPPIV and inflammation may contribute to HF development and progression.
- Severe Leptospirosis Features in the Spleen Indicate Cellular Immunosuppression Similar to That Found in Septic Shock(2019) DUARTE-NETO, Amaro Nunes; CRODA, Julio; PAGLIARI, Carla; SORIANO, Francisco Garcia; NICODEMO, Antonio Carlos; DUARTE, Maria Irma SeixasObjectives: To compare microscopic and immunologic features in the spleens of patients who died of pulmonary hemorrhage and shock caused by leptospirosis (11 cases) or Gram-positive/-negative bacterial septic shock (10 cases) to those from control spleens (12 cases from splenectomy). Methodology: Histological features in the red pulp and white pulp were analyzed using archived samples by a semi quantitative score. Immunohistochemistry was used for the recognition of immune cell markers, cytokines, caspase-3 and Leptospira antigens. Results: The control group differed significantly from the leptospirosis and septic shock patients which demonstrate strong similarities: diffuse congestion in the red pulp with a moderate to intense infiltration of plasma cells and polymorphonuclear cells; follicles with marked atrophy; high density of CD20(+) cells; low density of NK, TCD4(+) and active caspase-3 positive cells and strong expression of IL-10; leptospirosis patients had higher S100 and TNF-alpha positive cells in the spleen than the other groups. Conclusion: The results suggest that an immunosuppressive state develops at the terminal stage of severe leptospirosis with pulmonary hemorrhage and shock similar to that of patients with septic shock, with diffuse endothelial activation in the spleen, splenitis, and signs of disturbance in the innate and adaptive immunity in the spleen. The presence of leptospiral antigens in 73% of the spleens of the leptospirosis patients suggests the etiological agent contributes directly to the pathogenesis of the lesions. Our results support therapeutic approaches involving antibiotic and immunomodulatory treatments for leptospirosis patients and suggest that leptospirosis patients, which are usually young men with no co-morbidities, form a good group for studying sepsis and septic shock.
- Nonlinear Flow Sensor Calibration with an Accurate Syringe(2018) BISELLI, Paolo Jose Cesare; NOBREGA, Raquel Siqueira; SORIANO, Francisco GarciaFlow sensors are required for monitoring patients on mechanical ventilation and in respiratory research. Proper calibration is important for ensuring accuracy and can be done with a precision syringe. This procedure, however, becomes complex for nonlinear flow sensors, which are commonly used. The objective of the present work was to develop an algorithm to allow the calibration of nonlinear flow sensors using an accurate syringe. We first noticed that a power law equation could properly fit the pressure-flow relationship of nonlinear flow sensors. We then developed a software code to estimate the parameters for this equation using a 3 L syringe (calibration syringe). Finally, we tested the performance of a calibrated flow sensor using a different 3 L syringe (testing syringe) and a commercially available spirometer. After calibration, the sensor had a bias ranging from -1.7% to 3.0% and precision from 0.012 L to 0.039 L for volumes measured with the 3 L testing syringe. Calibrated sensor performance was at least as good as the commercial sensor. This calibration procedure can be done at the bedside for both clinical and research purposes, therefore improving the accuracy of nonlinear flow sensors.
- ENDOTOXEMIC MYOCARDIAL DYSFUNCTION: SUBENDOCARDIAL COLLAGEN DEPOSITION RELATED TO CORONARY DRIVING PRESSURE(2014) SORIANO, Francisco Garcia; GUIDO, Maria Carolina; BARBEIRO, Hermes Vieira; CALDINI, Elia Garcia; LORIGADOS, Clara Batista; NOGUEIRA, Antonio CarlosSepsis impairs the autoregulation of myocardial microcirculatory blood flow, but whether this impairment is correlated with myocardial remodeling is unknown. This study investigated the role of coronary driving pressure (CDP) as a determinant of microcirculatory blood flow and myocardial fibrosis in endotoxemia and sepsis. The study is composed of two parts: a prospective experimental study and an observational clinical study. The experimental study was performed on male Wistar rats weighing 300 to 320 g. Endotoxemia was induced in rats by lipopolysaccharide (LPS) injection (10 mg.kg(-1) intraperitoneally). Hemodynamic evaluation was performed 1.5 to 24 h after LPS injection by measuring the mean arterial pressure, CDP, left ventricular end-diastolic pressure, dP/dtmax, and dP/dtmin. Microspheres were also infused into the left ventricle to measure myocardial blood flow, and myocardial tissue was histologically assessed to analyze collagen deposition. The CDP, mean arterial pressure, and myocardial blood flow were reduced by 55%, 30%, and 70%, respectively, in rats 1.5 h after LPS injection compared with phosphate buffer saline injection (P < 0.05). The CDP was significantly correlated with subendocardial blood flow (r = 0.73) and fibrosis (r = 0.8). Left ventricular function was significantly impaired in the LPS-treated rats, as demonstrated by dP/dtmax (6,155 +/- 455 vs. 3,746 +/- 406 mmHg.s(-1), baseline vs. LPS; P < 0.05) and dP/dtmin (-5,858 +/- 236 vs. -3,516 +/- 436 mmHg.s(-1), baseline vs. LPS; P < 0.05). The clinical study was performed on 28 patients with septic shock analyzed for CDP. The CDP data and histological slices were collected from septic patients. In addition, the clinical data demonstrated fibrosis and 45% CDP reduction in nonsurvivors compared with survivors. In conclusion, the left ventricular subendocardial blood flow was positively correlated with CDP, and higher CDP was negatively correlated with myocardial collagen deposition. Thus, early reductions in myocardial blood flow and CDP facilitate late myocardial fibrosis in rats and likely in humans.
conferenceObject Baroreflex Sensitivity and Mortality in Septic dysfunction(2018) SANTOS, Fernando dos; NOGUEIRA, Antonio Carlos; BISELLI, Paolo; HOSHINO, Wagner; MOSTARDA, Cristiano Teixeira; ANGELIS, Katia De; SORIANO, Francisco Garcia; IRIGOYEN, Maria Claudia- Hypertonic saline solution reduces the inflammatory response in endotoxemic rats(2012) THEOBALDO, Mariana Cardillo; BARBEIRO, Hermes Vieira; BARBEIRO, Denise Frediani; PETRONI, Ricardo; SORIANO, Francisco GarciaOBJECTIVE: Volume replacement in septic patients improves hemodynamic stability. This effect can reduce the inflammatory response. The objective of this study was to evaluate the effect of 7.5% hypertonic saline solution versus 0.9% normal saline solution for volume replacement during an inflammatory response in endotoxemic rats. METHODS: We measured cytokines (serum and gut), nitrite, and lipid peroxidation (TBARS) as indicators of oxidative stress in the gut. Rats were divided into four groups: control group (C) that did not receive lipopolysaccharide; lipopolysaccharide injection without treatment (LPS); lipopolysaccharide injection with saline treatment (LPS + S); and lipopolysaccharide injection with hypertonic saline treatment (LPS + H). Serum and intestine were collected. Measurements were taken at 1.5, 8, and 24 h after lipopolysaccharide administration. RESULTS: Of the four groups, the LPS + H group had the highest survival rate. Hypertonic saline solution treatment led to lower levels of IL-6, IL-10, nitric oxide, and thiobarbituric acid reactive substances compared to 0.9% normal saline. In addition, hypertonic saline treatment resulted in a lower mortality compared to 0.9% normal saline treatment in endotoxemic rats. Volume replacement reduced levels of inflammatory mediators in the plasma and gut. CONCLUSION: Hypertonic saline treatment reduced mortality and lowered levels of inflammatory mediators in endotoxemic rats. Hypertonic saline also has the advantage of requiring less volume replacement.
- The role of nitric oxide in the epigenetic regulation of THP-1 induced by lipopolysaccharide(2016) RIOS, Ester Correia Sarmento; LIMA, Thais Martins de; MORETTI, Ana Iochabel Soares; SORIANO, Francisco GarciaAims: Changes in the gene expression are one of the molecular events involved in the Systemic of Inflammatory Response Syndrome during sepsis. The preconditioning with low doses of lipopolysaccharide (LPS) reduces the expression of pro-inflammatory genes leading to less tissue damage and better outcome. This hyporesponsive state called tolerance is associated to alterations in chromatin structure and nitric oxide (NO) production. In the current study, we demonstrated that tolerance induced by LPS was found to be NO-dependent and related to epigenetic changes. Main methods: THP-1 cells were cultivated in RPMI medium(Control), submitted to tolerance (500 ng/mL of LPS 24 h before challenge with 1000 ng/mL of LPS during 24 h Tolerant group) and challenge (1000 ng/mL of LPS during 24 h Directly challenged group). The analyses performed were: cytokines production, histone acetyl transferases/histone deacetylases (HAT/HDAC) activity, nitrosylation of HDAC-2 and -3, expression of acetylated histones H3 and H4. HDAC and Nitric Oxide Synthases (NOS) activities were inhibited with 30 mM trichostatin (TSA) and 100 mu M LNAME, respectively. Key findings: Administration of low doses of LPS repressed the production of IL-6 and IL-10, however this effect was abolished with the inhibition of NOS activity and by TSA in the case of IL-10. Tolerance modulates the activity of HAT and, consequently, the acetylation of histones H3 and H4. Inhibition of NO decreases acetylation of Histones. The HDACs 2 and 3 were nitrosylated after the tolerance induction. Significance: The tolerance to LPS regulates the cytokine production by modulating chromatin structure and this event is NO dependent.
- Plasma cytokine expression after lower-limb compression in rats(2015) SGARBI, Mauricio Wanderley Moral; SILVA JÚNIOR, Bomfim Alves; PERES, Carmem Maldonado; LOUREIRO, Tatiana Carolina Alba; CURI, Rui; SORIANO, Francisco Garcia; RIBEIRO, Daniel Araki; VELASCO, Irineu TadeuOBJECTIVES: Muscle injury due to crushing (muscle compression injury) is associated with systemic manifestations known as crush syndrome. A systemic inflammatory reaction may also be triggered by isolated muscle injury. The aim of this study was to investigate the plasma levels of interleukins (IL) 1, 6 and 10 and tumor necrosis factor alpha (TNF-α), which are markers for possible systemic inflammatory reactions, after isolated muscle injury resulting from lower-limb compression in rats. METHODS: Male Wistar rats were subjected to 1 h of compression of their lower limbs by means of a rubber band. The plasma levels of IL 1, 6 and 10 and TNF-α were measured 1, 2 and 4 h after the rats were released from compression. RESULTS: The plasma levels of IL 10 decreased in relation to those of the other groups, with a statistically significant difference (p < 0.05). The method used did not detect the presence of IL 1, IL 6 or TNF-α. CONCLUSION: Our results demonstrated that the changes in plasma levels of IL 10 that were found may have been a sign of the presence of circulating interleukins in this model of lower-limb compression in rats.
- Crotoxin modulates inflammation and macrophages? functions in a murine sepsis model(2022) BRETONES, Marisa Langeani; SAMPAIO, Sandra Coccuzzo; BARBEIRO, Denise Frediani; ARIGA, Suely K. Kubo; SORIANO, Francisco Garcia; LIMA, Thais Martins deSepsis is a syndrome of physiological and biochemical abnormalities induced by an infection that represents a major public health concern. It involves the early activation of inflammatory responses. Crotoxin (CTX), the major toxin of the South American rattlesnake Crotalus durissus terrificus venom, presents longstanding antiinflammatory properties. Since immune system modulation may be a strategic target in sepsis management, and macrophages' functional and secretory activities are related to the disease's progression, we evaluated the effects of CTX on macrophages from septic animals. Balb/c male mice submitted to cecal ligation and puncture (CLP) were treated with CTX (0.9 mu g/animal, subcutaneously) 1 h after the procedure and euthanized after 6 h. We used plasma samples to quantify circulating cytokines and eicosanoids. Bone marrow differentiated macrophages (BMDM) were used to evaluate the CTX effect on macrophages' functions. Our data show that CTX administration increased the survival rate of the animals from 40% to 80%. Septic mice presented lower plasma concentrations of IL-6 and TNF-alpha after CTX treatment, and higher concentrations of LXA4, PGE2, and IL-1 beta. No effect was observed in IL-10, IFN-gamma, and RD1 concentrations. BMDM from septic mice treated with CTX presented decreased capacity of E. coli phagocytosis, but sustained NO and H2O2 production. We also observed higher IL-6 concentration in the culture medium of BMDM from septic mice, and CTX induced a significant reduction. CTX treatment increased IL-10 production by macrophages as well. Our data show that the protective effect of CTX in sepsis mortality involves modulation of macrophage functions and inflammatory mediators' production.