THAIS MARTINS DE LIMA
Projetos de Pesquisa
Unidades Organizacionais
LIM/51 - Laboratório de Emergências Clínicas, Hospital das Clínicas, Faculdade de Medicina
LIM/02 - Laboratório de Anatomia Médico-Cirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/02 - Laboratório de Anatomia Médico-Cirúrgica, Hospital das Clínicas, Faculdade de Medicina
10 resultados
Resultados de Busca
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- Phagocytic activity of LPS tolerant macrophages(2014) LIMA, Thais Martins de; SAMPAIO, Sandra Coccuzzo; PETRONI, Ricardo; BRIGATTE, Patricia; VELASCO, Irineu Tadeu; SORIANO, Francisco GarciaEndotoxin tolerance is defined as a reduced capacity of the host to respond to LPS activation following a first exposure to this stimulus. It affects all leukocytes and regarding macrophages, most studies focus on the reduced ability of these cells to secrete pro-inflammatory cytokines. Therefore, we evaluated other macrophages functions (fungicidal capacity, reactive oxygen species production and antigen presentation) in cells from tolerant mice. We have performed a tolerance model in our laboratory that does not stimulate directly the place from where the cells will be removed (peritoneal cavity). Mouse received subcutaneous injections of LPS in the scruff for 5 days and we analyze the capacity of peritoneal macrophages to phagocyte using three different receptors: Fc, C3b and mannose receptors. We found a reduction in the phagocytosis of erythrocytes and Candida albicans related to the Fc and mannose receptors. These differences can be due to a macrophage reprogramming, as demonstrated by altered expression of cytokines and chemokines. Despite this reduction in phagocytosis capacity, macrophages from tolerant animals exhibited enhanced hydrogen peroxide production and expression of antigen presentation molecules, suggesting that their ability to combat an infection is improved. In summary, our data indicates that LPS tolerance drives macrophages from a predominant release of proinflammatory mediators that amplify inflammation and host damage toward a better killing and antigen presentation state.
- 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.
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.conferenceObject Lipid structures as biomarkers in septic shock: a new road to travel(2014) SILVA, F. Pinheiro Da; CATALDI, T.; LIMA, T. M. de; STARZYNSKI, P. N.; BARBEIRO, H. V.; LABATE, M. V.; MACHADO, M. C. C.; VELASCO, I. T.; SOUZA, H. P. de; LABATE, C. A.- Antimicrobial peptide LL-37 participates in the transcriptional regulation of melanoma cells(2016) MUNOZ, Mindy; CRASKE, Madeleine; SEVERINO, Patricia; LIMA, Thais Martins de; LABHART, Paul; CHAMMAS, Roger; VELASCO, Irineu Tadeu; MACHADO, Marcel Cerqueira Cesar; EGAN, Brian; NAKAYA, Helder I.; SILVA, Fabiano Pinheiro daAntimicrobial peptides are an ancient family of molecules that emerged millions of years ago and have been strongly conserved during the evolutionary process of living organisms. Recently, our group described that the human antimicrobial peptide LL-37 migrates to the nucleus, raising the possibility that LL-37 could directly modulate transcription under certain conditions. Here, we showed evidence that LL-37 binds to gene promoter regions, and LL-37 gene silencing changed the transcriptional program of melanoma A375 cells genes associated with histone, metabolism, cellular stress, ubiquitination and mitochondria.
- IMPACT OF TIME ON FLUID RESUSCITATION WITH HYPERTONIC SALINE (NACL 7.5%) IN RATS WITH LPS-INDUCED ACUTE LUNG INJURY(2015) PETRONI, Ricardo Costa; BISELLI, Paolo Jose Cesare; LIMA, Thais Martins de; VELASCO, Irineu Tadeu; SORIANO, Francisco GarciaAcute lung injury (ALI) is a common complication associated with septic shock that directly influences the prognosis of sepsis patients. Currently, one of the main supportive treatment modalities for septic shock is fluid resuscitation. The use of hypertonic saline (HS: 7.5% NaCl) for fluid resuscitation has been described as a promising therapy in experimental models of sepsis-induced ALI, but it has failed to produce similar results in clinical practice. Thus, we compared experimental timing versus clinical timing effectiveness (i.e., early vs. late fluid resuscitation) after the inflammatory scenario was established in a rat model of bacterial lipopolysaccharide-induced ALI. We found that late fluid resuscitation with hypertonic saline (NaCl 7.5%) did not reduce the mortality rates of animals compared with the mortality late associated with early treatment. Late fluid resuscitation with both hypertonic and normal saline increased pulmonary inflammation, decreased pulmonary function, and induced pulmonary injury by elevating metalloproteinase-2 and metalloproteinase-9 activity and collagen deposition in the animals, unlike early treatment. The animals with lipopolysaccharide-induced ALI that received late resuscitation with any kind of fluids demonstrated aggravated pulmonary injury and respiratory function. Moreover, we showed that the therapeutic window for a beneficial effect of fluid resuscitation with hypertonic saline is very narrow.
- PPAR gamma expression is increased in systemic lupus erythematosus patients and represses CD40/CD40L signaling pathway(2011) OXER, D. S.; GODOY, L. C.; BORBA, E.; LIMA-SALGADO, T.; PASSOS, L. A.; LAURINDO, I.; KUBO, S.; BARBEIRO, D. F.; FERNANDES, D.; LAURINDO, F. R.; VELASCO, I. T.; CURI, R.; BONFA, E.; SOUZA, H. P.Systemic lupus erythematosus (SLE) is a heterogeneous disease involving several immune cell types and pro-inflammatory signals, including the one triggered by binding of CD40L to the receptor CD40. Peroxisome-proliferator activated receptor gamma (PPAR gamma) is a transcription factor with anti-inflammatory properties. Here we investigated whether CD40 and PPAR gamma could exert opposite effects in the immune response and the possible implications for SLE. Increased PPAR gamma mRNA levels were detected by real-time PCR in patients with active SLE, compared to patients with inactive SLE PPAR gamma/GAPDH mRNA = 2.21 +/- 0.49 vs. 0.57 +/- 0.14, respectively (p < 0.05) or patients with infectious diseases and healthy subjects (p < 0.05). This finding was independent of the corticosteroid therapy. We further explored these observations in human THP1 and in SLE patient-derived macrophages, where activation of CD40 by CD40L promoted augmented PPAR gamma gene transcription compared to non-stimulated cells (PPAR gamma/GAPDH mRNA = 1.14 +/- 0.38 vs. 0.14 +/- 0.01, respectively; p < 0.05). This phenomenon occurred specifically upon CD40 activation, since lipopolysaccharide treatment did not induce a similar response. In addition, increased activity of PPAR gamma was also detected after CD40 activation, since higher PPAR gamma-dependent transcription of CD36 transcription was observed. Furthermore, CD40L-stimulated transcription of CD80 gene was elevated in cells treated with PPAR gamma-specific small interfering RNA (small interfering RNA, siRNA) compared to cells treated with CD40L alone (CD80/GAPDH mRNA = 0.11 +/- 0.04 vs. 0.05 +/- 0.02, respectively; p < 0.05), suggesting a regulatory role for PPAR gamma on the CD40/CD40L pathway. Altogether, our findings outline a novel mechanism through which PPAR gamma regulates the inflammatory signal initiated by activation of CD40, with important implications for the understanding of immunological mechanisms underlying SLE and the development of new treatment strategies. Lupus (2011) 20, 575-587.
- Hypertonic Saline (NaCl 7.5 %) Reduces LPS-Induced Acute Lung Injury in Rats(2015) PETRONI, Ricardo Costa; BISELLI, Paolo Jose Cesare; LIMA, Thais Martins de; THEOBALDO, Mariana Cardillo; CALDINI, Elia Tamaso; PIMENTEL, Rosangela Nascimento; BARBEIRO, Hermes Vieira; KUBO, Suely Ariga; VELASCO, Irineu Tadeu; SORIANO, Francisco GarciaAcute respiratory distress syndrome (ARDS) is the most severe lung inflammatory manifestation and has no effective therapy nowadays. Sepsis is one of the main illnesses among ARDS causes. The use of fluid resuscitation is an important treatment for sepsis, but positive fluid balance may induce pulmonary injury. As an alternative, fluid resuscitation with hypertonic saline ((HS) NaCl 7.5 %) has been described as a promising therapeutical agent in sepsis-induced ARDS by the diminished amount of fluid necessary. Thus, we evaluated the effect of hypertonic saline in the treatment of LPS-induced ARDS. We found that hypertonic saline (NaCl 7.5 %) treatment in rat model of LPS-induced ARDS avoided pulmonary function worsening and inhibited type I collagen deposition. In addition, hypertonic saline prevented pulmonary injury by decreasing metalloproteinase 9 (MMP-9) activity in tissue. Focal adhesion kinase (FAK) activation was reduced in HS group as well as neutrophil infiltration, NOS2 expression and NO content. Our study shows that fluid resuscitation with hypertonic saline decreases the progression of LPS-induced ARDS due to inhibition of pulmonary remodeling that is observed when regular saline is used.
- ENDOTOXIN TOLERANCE DRIVES NEUTROPHIL TO INFECTIOUS SITE(2014) ARIGA, Suely Kubo; ABATEPAULO, Fatima Bernardes; MELO, Edielle Sant Anna; VELASCO, Irineu Tadeu; SILVA, Fabiano Pinheiro da; LIMA, Thais Martins de; SORIANO, Francisco GarciaThe objective of this randomized animal study and laboratory investigation was to investigate whether lipopolysaccharide tolerance redirects neutrophil migration between organs. Male BALB/c mice received subcutaneous injections of lipopolysaccharide (1 mg/kg) for 5 days, followed by cecal ligation and puncture (CLP). Cytokines and adhesion molecules were measured after tolerance and CLP challenge. Increased numbers of neutrophils were observed in the peritoneal cavity of tolerant mice, which was associated with increased levels of adhesion molecules and chemokines. In contrast, nontolerant mice accumulated higher numbers of neutrophils in the lungs compared with those in the peritoneal cavity. Neutrophil function accessed by hydrogen peroxide production from neutrophils recovered from peritoneal cavity showed that tolerance increased the capacity to produce hydrogen peroxide. Mortality was reduced in tolerant animals. This study demonstrated that tolerance reduces leukocyte accumulation in the lung after CLP by redirecting neutrophils to the site of infection.
conferenceObject PGC-1 alpha is a Valuable Tool to Differentiate Inflammation From Infection in Acute Pancreatitis(2012) LLIMONA, F.; LIMA-SALGADO, T. M.; MORETTI, A. L.; THEOBALDO, M.; JUKEMURA, J.; MACHADO, M. C. C.; VELASCO, I. T.; SOUZA, H. P.Background: Differentiate sepsis from the systemic inflammation caused by AP remains a clinical challenge. We hypothesized that transcription coactivator PGC-1>, a regulator of mitochondrial biogenesis and function, would be distinctly expressed during inflammation or infection, being useful to differentiate these two conditions. Methods: Acute pancreatitis(AP) was induced by retrograde injection o,5 ml of 5% sodium taurocholate into the main pancreatic duct.. PGC-1> mRNA.was evaluated by using a quantitayive Real-time PCR Macrophages were obtained by washing the peritoneum with PBS and placed in culture for 2h. and exposed to lipopolysaccharide, zymosan or vehicle. In another set of experiments, macrophages were transfected with antisense against PGC-1> Cecal ligation puncture (CLP) was used to establish a model of infected peritonitis. Results: In AP animals a marked increase in PGC-1> mRNA levels in circulating leukocytes was observed 48h after the surgical procedure, a time when bacteremia is present. Antibiotic treatment abolished PGC-1> up-regulation. Moreover, PGC-1> expression was higher in peritoneal macrophages from animals submitted to a bacterial insult (CLP) than in animals with acute pancreatitis .In macrophages, we could observe that PGC-1> expression is more prominent in the presence of a phagocytic stimulus (zymosan) compared to an aseptic inflammation induce by lipopolysaccharide. Moreover, abolishing PGC-1> expression with antisense impaired zymosan phagocytosis. Conclusion: Together these findings suggest that PGC-1> 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 in patients with acute pancreatitis.