HERALDO POSSOLO DE SOUZA
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina - Docente
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/02 - Laboratório de Anatomia Médico-Cirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/51 - Laboratório de Emergências Clínicas, Hospital das Clínicas, Faculdade de Medicina
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/02 - Laboratório de Anatomia Médico-Cirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/51 - Laboratório de Emergências Clínicas, Hospital das Clínicas, Faculdade de Medicina
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conferenceObject Inflammatory and antioxidant response in obese septic shock patients(2013) VICTORINO, Vanessa Jacob; BARBEIRO, Hermes Vieira; BARBEIRO, Denise Frediani; SILVA, Fabiano Pinheiro; SOUZA, Heraldo PossoloThere is no consensus about the influence of obesity on sepsis. Hence, we evaluated the inflammatory and antioxidant response in obese patients (body mass index > 30) with septic shock compared to non-infected obese and non-obese septic patients. Blood samples were obtained from 27 critically ill patients admitted to ICUs in Clinics Hospital, Universidade de Sao Paulo. Cytokines were measured by ELISA Milliplex and antioxidant activity by colorimetric methods. There are small differences in the cytokine profiles in obese septic patients (n=6), compared to obese non-infected ones (n=10). Only FGF2, TGF-α, IFN-α2, IFN-{gamma}, IL-10, MCP-3, IL-13 and IL-15 presented significantly higher levels in septic patients. Interestingly, there was a marked increase in superoxide dismutase (SOD) and catalase (CAT) activity in erythrocytes from the septic group. Compared to their non-obese septic counterparts, septic obese patients presented significantly lower levels of FGF2, IL-4, TNF-β and VEGF. SOD activity was higher in this group, compared to non-obese patients. We concluded that obese patients with septic shock maintain cytokine levels similar to the ones observed in their non-obese counterparts, while increasing their antioxidant activity.conferenceObject Effect of low level laser therapy on lung mechanics and inflammatory response(2013) CURY, Vivian; LIMA, Thais; ARIGA, Suely; BARBEIRO, Denise; PINHEIRO, Nathalia; PRADO, Carla Maximo; MORETTI, Ana Iochabel; SOUZA, Heraldo PossoloconferenceObject Late remodeling of extracellular matrix after acute inflammatory injury or chronic distension(2012) PRIST, Iryna Hirata; SALLES, Alessandra Grassi; SALGADO, Thais M. de Lima; SOUZA, Heraldo Possolo DeExtracellular matrix remodeling is a crucial step in the healing process after inflammatory or infectious insult. We studied the role of matrix metalloproteinases in models of disease secondary to an acute inflammatory injury (burned skin) or chronic aggression (skin from obese patients submitted to gastroplasty). Skin samples were extracted using a 4 mm punch from abdomen of patients in late post-operative of bariatric surgery, recovered from third degree burns or control subjects. RNA was extracted by TRIzol and evaluated by quantitative PCR. MMPs activity was determined by zymography. In skin from burned patients, MMPs 2 and 9 expression was not different from control subjects. Obese patients present a higher MMP2 expression, compared to controls (2.4±0.56 x 1.0±0.1, respectively, p<0.05), however MMP9 mRNA was not detectable in these patients, even when conventional PCR was used. Interestingly, in spite of higher mRNA amounts, MMP2 activity was reduced in burned patients compared to controls (1.3±0.1 x 2.6±0.5 A.U., respectively, p<0.05), while MMP9 activity had a large variability, preventing any conclusion. We conclude that an acute inflammatory stimulus leads to late decreased MMP2 activity, what can explain the extensive fibrosis observed in these patients. In a more prolonged injury, due to chronic skin distension caused by obesity, MMP9 expression is affected leading to flabby skin deposits.- Cardioprotective mechanism of S-nitroso-N-acetylcysteine via S-nitrosated betadrenoceptor-2 in the LDLr-/- mice(2014) WANSCHEL, Amarylis Claudine Bonito Azeredo; CACERES, Viviane Menezes; MORETTI, Ana Iochabel Soares; BRUNI-CARDOSO, Alexandre; CARVALHO, Hernandes Faustino de; SOUZA, Heraldo Possolo de; LAURINDO, Francisco Rafael Martins; SPADARI, Regina Celia; KRIEGER, Marta HelenaPrevious studies from our group have demonstrated the protective effect of S-nitroso-N-acetylcysteine (SNAC) on the cardiovascular system in dyslipidemic LDLr-/- mice that develop atheroma and left ventricular hypertrophy after 15 days on a high fat diet. We have shown that SNAC treatment attenuates plaque development via the suppression of vascular oxidative stress and protects the heart from structural and functional myocardial alterations, such as heart arrhythmia, by reducing cardiomyocyte sensitivity to catecholamines. Here we investigate the ability of SNAC to modulate oxidative stress and cell survival in cardiomyocytes during remodeling and correlation with beta(2)-AR signaling in mediating this protection. Ventricular superoxide (O-2(-)) and hydrogen peroxide (H2O2) generation was measured by HPLC methods to allow quantification of dihydroethidium (DHE) products. Ventricular histological sections were stained using terminal dUTP nick-end labeling (TUNEL) to identify nuclei with DNA degradation (apoptosis) and this was confirmed by Western blot for cleaved caspase-3 and caspase-7 protein expression. The findings show that O-2(-) and H2O2 production and also cell apoptosis were increased during left ventricular hypertrophy (LVH). SNAC treatment reduced oxidative stress during on cardiac remodeling, measured by decreased H2O2 and O-2(-) production (65% and 52%, respectively), and a decrease in the ratio of p-Ser1177 eNOS/total eNOS. Left ventricle (LV) from SNAC-treated mice revealed a 4-fold increase in beta(2)-AR expression associated with coupling change to Gi; beta(2)-ARs-S-nitrosation (beta(2)-AR-SNO) increased 61%, while apoptosis decreased by 70%. These results suggest that the cardio-protective effect of SNAC treatment is primarily through its anti-oxidant role and is associated with beta(2)-ARs overexpression and beta(2)-AR-SNO via an anti-apoptotic pathway.
- Novel role of TLR4 in NAFLD development: Modulation of metabolic enzymes expression(2015) FERREIRA, Darkiane Fernandes; FIAMONCINI, Jarlei; PRIST, Iryna Hirata; ARIGA, Suely Kubo; SOUZA, Heraldo Possolo de; LIMA, Thais Martins deThe rise in the prevalence of obesity and metabolic syndrome turned NAFLD as the most common cause of chronic liver diseases worldwide. Although the role of toll like receptors, especially TLR4, as activators of inflammatory pathways in liver diseases is well established, our goal was to investigate if TLR4 activation could modulate metabolic lipid pathways and alter the onset of NAFLD. We used LDL receptor-deficient mice (LDLrKO) fed with an atherogenic diet as a model. The role of TLR4 activation was evaluated by crossing LDLrKO mice with the TLR4 knockout mice. Animals were fed for 12 weeks with high-fat high-cholesterol diet (HFD) containing 18% saturated fat and 1.25% cholesterol. TLR4/LDLr KO mice presented lower triacylglyceride (TAG) plasma levels when compared to LDLrKO, despite the type of diet ingested. HFD induced TAG and cholesterol accumulation in the liver of all mice genotypes studied, but TLR4/LDLr KO presented lower TAG accumulation than LDLrKO mice. Gene expression of TAG synthesis enzymes (ApoB100, MTTP, GPAT1 and GPAT4) was not differentially altered in TLR4/LDLr KO and LDLrKO mice. On the other hand, TLR4 deficiency enhanced the expression of several enzymes involved in the oxidation of fatty acids, as follows: ACOX, CPT-1, MTPa, MTBb, PBE and 3-ketoacyl-CoA thiolase. Acyl-camitine plasma profile showed an increase in C0 and C2 concentration in TLR4/LDLr KO group, corroborating the hypothesis of increased fat oxidation. Our results indicate that TLR4 may have an important role in the onset of steatosis, once its depletion enhances fatty acid oxidation in the liver of mice, preventing triglyceride accumulation.
conferenceObject Effect of low level laser therapy on acute lung injury(2012) CURY, Vivian; LIMA-SALGADO, Thais; PINHEIRO, Natalia; PRADO, Carla Maximo; ASSIS, Livia; MORETTI, Ana Iochabel; SOUZA, Heraldo PossoloLow level laser therapy (LLLT) is prescribed as adjuvant therapy for inflammatory diseases. Hence, we examined whether LLLT may ameliorate acute lung injury (ALI) induced by intratracheal LPS instillation. C57 black mice (n=10 per group) were treated with intratracheal LPS (5mg/kg) or PBS. Six hours after instillation, two groups (PBS and LPS) were irradiated with laser at 660 nm, power output 30mW, fluency 10J/cm2. We observed a marked decrease in the number of cells recovered by bronchoalveolar lavage in LPS + LLLT animals compared to LPS alone (2.0±0.8 x 4.4±1.3, respectively p<0.05). LLLT also decreased the number of inflammatory cells infiltrated in lung interstitium (49.6±3.15 x 71.8±3.92), p<0.05). There was also a decrease in the expression of F4/80 (macrophage surface marker) and MCP-1 (monocyte chemoattractant protein-1), detected by quantitative PCR, in animals submitted to LPS + LLLT, when compared to animals that received only LPS. A marked decrease in cytokines secretion (IL1β, TNFα, IL6, IL10) was also observed in LPS+LLLT group. No difference was observed in animals that received PBS, regardless of LLLT. Therefore, LLLT decreases pulmonary inflammatory cell infiltration, cytokines and chemokines secretion in an experimental model of ALI, supporting the notion that laser therapy attenuates inflammatory intensity, what can contribute to accelerate ALI resolution.- PGC-1 alpha Expression Is Increased in Leukocytes in Experimental Acute Pancreatitis(2014) LLIMONA, Flavia; LIMA, Thais Martins de; MORETTI, Ana Iochabel; THEOBALDO, Mariana; JUKEMURA, Jose; VELASCO, Irineu Tadeu; MACHADO, Marcel C. C.; SOUZA, Heraldo PossoloSevere acute pancreatitis (AP) induces a systemic inflammatory disease that is responsible for high mortality rates, particularly when it is complicated by infection. Therefore, differentiating sepsis from the systemic inflammation caused by AP is a serious clinical challenge. Considering the high metabolic rates of leukocytes in response to stress induced by infection, we hypothesized that the transcription coactivator peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1 alpha), a master regulator of mitochondrial biogenesis and function, would be distinctly expressed during inflammation or infection and, therefore, could constitute a useful marker to differentiate between these two conditions. Rats were subjected to injection of taurocholate into the main pancreatic duct, which caused a severe AP with high amylase levels and white blood cell counts. In these animals, a marked increase in PGC-1 alpha mRNA levels in circulating leukocytes was observed 48 h after the surgical procedure, a time when bacteremia is present. Antibiotic treatment abolished PGC-1 alpha up-regulation. Moreover, PGC-1 alpha expression was higher in peritoneal macrophages from animals subjected to a bacterial insult (cecal ligation and puncture) than in animals with AP. In isolated macrophages, we also observed that PGC-1 alpha expression is more prominent in the presence of a phagocytic stimulus (zymosan) when compared to lipopolysaccharide-induced aseptic inflammation. Moreover, abolishing PGC-1 alpha expression with antisense oligos impaired zymosan phagocytosis. Together, these findings suggest that PGC-1 alpha is differentially expressed during aseptic inflammation and infection and that it is necessary for adequate phagocytosis. These results could be useful in developing new tests for differentiating infection from inflammation for clinical purposes in patients with AP.
- Neutrophils LL-37 migrate to the nucleus during overwhelming infection(2013) SILVA, Fabiano Pinheiro da; MEDEIROS, Maria Cristina Rodrigues; SANTOS, Angela Batista Gomes dos; FERREIRA, Marcelo Alves; GARIPPO, Ana Lucia; CHAMMAS, Roger; CALDINI, Elia; VELASCO, Irineu Tadeu; SOUZA, Heraldo Possolo de; MACHADO, Marcel Cerqueira CesarLL-37 is the only cathelicidin produced by human cells. It is secreted by a variety of cell types, including monocyte/macrophages, neutrophils, mast cells, keratinocytes and epithelial cells, acting on the extracellular milieu by directly killing bacteria or boosting innate immunity. Here, we show that LL-37 translocates to the nucleus following overwhelming infection, putting in evidence that its role may be even broader, with new potential important implications to cell biology. Future studies are necessary to address if LL-37 is able to induce or affect transcription, since it can lead to a novel cell signaling pathway that probably will contribute to the understanding of complex diseases.
conferenceObject Expression of peroxisome proliferator activated receptor gamma coactivator 1 (PGC-1) on the immune response to bacteria(2012) NERO, Luis Guilherme Del; MARTA, Guilherme; LIMA-SALGADO, Thais; KUBO, Sueli; LLIMONA, Flavia; VELASCO, Irineu Tadeu; SOUZA, HeraldoIntroduction/Objective: Inflammatory response during sepsis requires energy expenditure from immune cells. Since the transcription coactivator PGC-1 controls cell energy homeostasis, we aimed to determine whether PGC-1 may modulate the immune response in an experimental model of sepsis. Methods: Live bacteria were injected intraperitoneally in Balb/C mice and PGC-1β expression was evaluated by quantitative PCR in peritoneal macrophages. Further, mice (20 animals in each group) were submitted to cecal ligation and puncture (CLP). Group 1 received intraperitoneal injections of antisense oligonucleotide (ASO) against PGC-1β (3,0 nmol) three days before and three days after CLP. Group 2 was given no specific treatment. The animals were followed for 72 hours and mortality was evaluated every 12 hours. Results: Increased PGC-1β expression was observed in macrophages from animals exposed to bacteria compared to controls (2.7±0.5 vs. 1.0±0.2, respectively, p<0.05). We further evaluated whether PGC-1β absence would interfere with the response to acute bacterial aggression in vivo. Mice from Group 1, where PGC-1β expression was blocked, showed an 80% mortality after 72 hours, while animals from Group 2 had a mortality rate of 63% (p=0,7714). Conclusions: PGC-1β is up-regulated during bacterial infection, however, abolishing PGC-1β expression did not affect mortality of septic mice.- Neuropeptide Downregulation in Sepsis(2014) SILVA, Fabiano Pinheiro da; MACHADO, Marcel Cerqueira Cesar; SALLET, Paulo Clemente; ZAMPIERI, Fernando Godinho; GOULART, Alessandra Carvalho; TORGGLER FILHO, Francisco; BARBEIRO, Hermes Vieira; VELASCO, Irineu Tadeu; CRUZ NETO, Luiz Monteiro da; SOUZA, Heraldo Possolo deNeuropeptides are an extremely conserved arm of neurobiology. Despite their effects as neurohormones and neurotransmitters, a multitude of other effects have been described, putting in evidence their importance as regulators of immune responses, such as chemotaxis, oxidative burst, pro-inflammatory signaling, and many others. The effects of neuropeptides in the pathophysiology of sepsis, however, remain poorly investigated. A prospective cohort study to investigate the effects of neuropeptides in sepsis was carried out. Here, we describe that neuropeptides are downregulated during septic shock. We propose that it may be a protective mechanism of the host to avoid further inflammatory injury.