Navegando por Palavras-chave "neutrophils"

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    Apoptosis of leukocytes: Basic concepts and implications in uremia
    (Blackwell Science Inc, 2001-02-01) Jaber, Bertrand L. [UNIFESP]; Cendoroglo Neto, Miguel [UNIFESP]; Balakrishnan, Vaidyanathapuram S.; Perianayagam, Mary C.; King, Andrew J.; Pereira, Brian JG; Univ Fed Ceara; Hosp Clin Montevideo; Universidade Federal de São Paulo (UNIFESP); Universidade Federal Fluminense (UFF)
    Circulating blood leukocytes have short life expectancies and end their lives by committing programmed cell death or apoptosis. Apoptosis is an active form of cell death that is initiated by a number of stimuli and is intricately regulated. Apoptosis in both excessive and reduced amounts has pathological implications. Evidence suggests that apoptosis may play a role in the pathophysiology of immune dysfunction in uremia. Indeed, accelerated programmed cell death has been observed in lymphocytes, monocytes, and polymorphonuclear leukocytes among patients with chronic renal failure. This may be due in part to the retention of uremic toxins. The aim of this article is to review the evidence for accelerated leukocyte apoptosis, key regulatory apoptotic pathways, and the possible role of this highly organized process in the pathogenesis of immune dysfunction in uremia.
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    Avaliação do efeito da hipotermia por crioimersão corporal, nos neutrófilos e linfócitos sanguíneos de ratos submetidos ao exercício físico agudo
    (Associação Brasileira de Hematologia e Hemoterapia e Terapia Celular, 2008-12-01) Bachur, José Alexandre; Quemelo, Paulo R.; Bachur, Cynthia A. K.; Domenciano, Julio C.; Martins, Carlos H. G.; Stoppa, Marcos A.; Barros Neto, Turibio Leite de [UNIFESP]; Garcia, Sérgio B.; Universidade de Franca Fisioterapia Unifran. Lab. de Estudos da Recuperação Orgânica e Funcional; Universidade de Franca; Universidade Federal de São Paulo (UNIFESP); Universidade de São Paulo (USP)
    Systemic stress induced by exercise increases bioactive substances in plasma which leads to neutrophilic mobilization. Cryotherapy causes a decrease in the inflammatory reaction and attenuates high blood perfusion after exercise. The objective of this work was to analyze the influence of cold water immersion (CWI) after acute exercise on neutrophil and lymphocyte mobilization. A control group of rats (AI) was kept at rest and a second group (AII) was submitted to CWI at 10º C for 10 minutes. The animals of Groups BI, BII, BIII and BIV were submitted to acute exercise which consisted in swimming in water at 31º C for 100 minutes with a load equivalent to 5% of the body weight. Groups CI, CII, CIII and CIV were submitted to CWI immediately after acute exercise. The animals were sacrificed at 6 (I), 12 (II), 24 (III) and 48 (IV) hours after the exercise and neutrophil and lymphocyte cells were counted for all groups by optic microscopy. The Student t-test was used for statistical analysis with a significance level of p< 0.05. A significant increase in the number of neutrophils was observed in Groups AII, BI, BII, BIII, BIV, CI, CII and CIII compared to AI. The neutrophil count of the CIV Group was similar to the Control Group. There was a significant drop in the number of lymphocytes in Groups BII, BIII, BIV, CI and CII when compared to Group AI. The lymphocyte count of Groups AII, BI, CIII and CIV were similar to the Control Group. The changes in neutrophil and lymphocyte counts caused by acute exercise were reverted to normal at 24 hours by cold water immersion.
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    Chronic granulomatous disease in Latin American patients: Clinical spectrum and molecular genetics
    (Wiley-Blackwell, 2006-02-01) Agudelo-Florez, P.; Prando-Andrade, C. C.; Lopez, J. A.; Costa-Carvalho, B. T.; Quezada, A.; Espinosa, F. J.; Paiva, MAD; Roxo, P.; Grumach, A.; Jacob, C. A.; Carneiro-Sampaio, MMS; Newburger, P. E.; Condino-Neto, A.; Universidade de São Paulo (USP); Universidade Estadual de Campinas (UNICAMP); Universidade Federal de São Paulo (UNIFESP); Univ Chile; Natl Inst Pediat; Rio de Janeiro State Employees Hosp; Univ Massachusetts
    Background. Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by early onset of recurrent and severe infections. the molecular defects causing CGD are heterogeneous and lead to absence, low expression, or malfunctioning of one of the phagocyte NADPH oxidase components. the aim of this study was to analyze the clinical features and to investigate the molecular genetic defects of Latin American patients with CGD.Procedures. the study included 14 patients. the diagnosis was based on a history of recurrent severe infections, impaired respiratory burst, and the demonstration of an underlying mutation by single strand conformation polymorphism (SSCP) or RT-PCR analysis, followed by genomic DNA or cDNA sequencing.Results. Seven unrelated patients were found to have the X-linked form of CGD (X-CGD). Heterogeneous mutations affected the CYBB gene: two insertions, one substitution, and four splice site defects; two of them are novel. Seven patients presented with one of the autosomal recessive forms of CGD (A47-CGD); all had the most common mutation, a Delta GT deletion in exon 2 of the NCF1 gene. Pneumonia was the most frequent clinical feature, followed by pyoderma, sinusitis, otitis, and liver abscess. Patients with X-CGD were more likely to have initial infections before age 2 years and to have inflammatory obstructive granulomas later. None of the patients had severe adverse reactions to BCG immunization.Conclusions. X-CGD patients from Latin America showed a high degree of molecular heterogeneity, including two novel Mutations. Their clinical characteristics included early onset of infections and eventual obstructive granulomas. A47-CGD represented 50% of the reported cases, a higher prevalence than reported in other series.
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    Comparative analysis of the pathological events involved in immune and non-immune TRALI models
    (Wiley-Blackwell, 2012-11-01) Tamarozzi, M. B.; Soares, S. G.; Sa-Nunes, A.; Paiva, H. H.; Saggioro, F. P.; Garcia, A. B.; Lucena-Araujo, A. R.; Falcao, R. P.; Bordin, J. O. [UNIFESP]; Rego, E. M.; Universidade de São Paulo (USP); Invent Biotecnol; Universidade Federal de São Paulo (UNIFESP)
    Background and Objectives Transfusion-related acute lung injury (TRALI) is characterized by leukocyte transmigration and alveolar capillary leakage shortly after transfusion. TRALI pathogenesis has not been fully elucidated. in some cases, the infusion of alloantibodies (immune model), whereas in others the combination of neutrophil priming by proinflammatory molecules with the subsequent infusion of biological response modifiers (BRMs) in the hemocomponent (non-immune model) have been implicated. Our aim was to compare the pathological events involved in TRALI induced by antibodies or BRMs using murine models. Materials and Methods in the immune model, human HNA-2+ neutrophils were incubated in vitro with a monoclonal antibody (anti-CD177, clone 7D8) directed against the HNA-2 antigen and injected i.v. in NOD/SCID mice. in the non-immune model, BALB/c mice were treated with low doses of lipopolysaccharide (LPS) followed by platelet-activating factor (PAF) infusion 2 h later. Forty minutes after PAF administration, or 6 h after neutrophil injection, lungs were isolated and histological analysis, determination of a variety of cytokines and chemokines including keratinocyte-derived chemokine (KC), MIP-2, the interleukins IL-1 beta, IL-6, IL-8 as well as TNFa, cell influx and alveolar capillary leakage were performed. Results in both models, characteristic histological findings of TRALI and an increase in KC and MIP-2 levels were detected. in contrast to the immune model, in the non-immune model, there was a dramatic increase in IL-1 beta and TNFa. However, capillary leakage was only detected if PAF was administrated. Conclusions Regardless of the triggering event(s), KC, MIP-2 and integrins participate in TRALI pathogenesis, whereas PAF is essential for capillary leakage when two events are involved.
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    An essential role for mast cells as modulators of neutrophils influx in collagen-induced arthritis in the mouse
    (Nature Publishing Group, 2011-01-01) Pimentel, Tatiana Aparecida [UNIFESP]; Franco Sampaio, Andre Luiz; D'Acquisto, Fulvio; Perretti, Mauro; Oliani, Sonia Maria [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Queen Mary Univ London; FarManguinhos FIOCRUZ; São Paulo State Univ UNESP
    Mast cells are involved in immune disorders so that many of the proinflammatory and tissue destructive mediators produced by these cells have been implicated in the pathogenesis of rheumatoid arthritis. This scenario prompted us to investigate the correlation between mast cell degranulation and neutrophil influx within the digits and knees joints of arthritic mice assessing what could be the functional role(s) of joint mast cells in the response to collagen immunization. DBA/1J mice were submitted to collagen-induced arthritis and disease was assessed on day 21, 32 and 42 post-immunization. Pharmacological treatment with the glucocorticoid prednisolone, commonly used in the clinic, and nedocromil, a mast cell stabilizer, was performed from day 21 to 30. Arthritis develop after immunization, gradually increased up to day 42. Neutrophil infiltration peaked on day 32 and 21, in the digits and knees, respectively, showing an unequal pattern of recruitment between these tissues. This difference emerged for mast cells: they peaked in the digits on day 21, but a higher degree of degranulation could be measured in the knee joints. Uneven modulation of arthritis occurred after treatment of mice with prednisolone or nedocromil. Neutrophils migration to the tissue was reduced after both therapies, but only prednisolone augmented mast cell migration to the joints. Nedocromil exerted inhibitory properties both on mast cell proliferation and migration, more effectively on the digit joints. Thus, collagen induced an inflammatory process characterized by tissue mast cells activation and degranulation, suggesting a potential driving force in propagating inflammatory circuits yielding recruitment of neutrophils. However, the different degree of affected joint involvement suggests a time-related implication of digits and knees during collagen-induced arthritis development. These results provide evidence for local alterations whereby mast cells contribute to the initiation of inflammatory arthritis and may be targeted in intervention strategies. Laboratory Investigation (2011) 91, 33-42; doi:10.1038/labinvest.2010.140; published online 16 August 2010
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    The essential role of annexin A1 mimetic peptide in the skin allograft survival
    (Wiley-Blackwell, 2016) Teixeira, Rodrigo Antonio Parra [UNIFESP]; Mimura, Kallyne Kioko Oliveira [UNIFESP]; Araujo, Leandro Pires [UNIFESP]; Greco, Karin Vicente; Oliani, Sonia Maria [UNIFESP]
    Immunosuppressive drugs have a critical role in inhibiting tissue damage and allograft rejection. Studies have demonstrated the anti-inflammatory effects of the annexin A1 (AnxA1) in the regulation of transmigration and apoptosis of leucocytes. In the present study, an experimental skin allograft model was used to evaluate a potential protective effect of AnxA1 in transplantation survival. Mice were used for the skin allograft model and pharmacological treatments were carried out using either the AnxA1 mimetic peptide Ac2-26, with or without cyclosporine A (CsA), starting 3days before surgery until rejection. Graft survival, skin histopathology, leucocyte transmigration and expression of AnxA1 and AnxA5 post-transplantation were analysed. Pharmacological treatment with Ac2-26 increased skin allograft survival related with inhibition of neutrophil transmigration and induction of apoptosis, thereby reducing the tissue damage compared with control animals. Moreover, AnxA1 and AnxA5 expression increased after Ac2-26 treatment in neutrophils. Interestingly, the combination of Ac2-26 and cyclosporine A showed similar survival of transplants when compared with the cyclosporine A group, which could be attributed to a synergistic effect of both drugs. Investigations in vitro revealed that cyclosporine A inhibited extracellular-signal-regulated kinase (ERK) phosphorylation induced by Ac2-26 in neutrophils. Overall, the results suggest that AnxA1 has an essential role in augmenting the survival of skin allograft, mainly owing to inhibition of neutrophil transmigration and enhancement of apoptosis. This effect may lead to the development of new therapeutic approaches relevant to transplant rejection. Copyright (c) 2013 John Wiley & Sons, Ltd.
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    The essential role of annexin A1 mimetic peptide in the skin allograft survival
    (Wiley-Blackwell, 2016) Teixeira, Rodrigo Antonio Parra [UNIFESP]; Mimura, Kallyne Kioko Oliveira [UNIFESP]; Araujo, Leandro Pires [UNIFESP]; Greco, Karin Vicente; Oliani, Sonia Maria [UNIFESP]
    Immunosuppressive drugs have a critical role in inhibiting tissue damage and allograft rejection. Studies have demonstrated the anti-inflammatory effects of the annexin A1 (AnxA1) in the regulation of transmigration and apoptosis of leucocytes. In the present study, an experimental skin allograft model was used to evaluate a potential protective effect of AnxA1 in transplantation survival. Mice were used for the skin allograft model and pharmacological treatments were carried out using either the AnxA1 mimetic peptide Ac2-26, with or without cyclosporine A (CsA), starting 3days before surgery until rejection. Graft survival, skin histopathology, leucocyte transmigration and expression of AnxA1 and AnxA5 post-transplantation were analysed. Pharmacological treatment with Ac2-26 increased skin allograft survival related with inhibition of neutrophil transmigration and induction of apoptosis, thereby reducing the tissue damage compared with control animals. Moreover, AnxA1 and AnxA5 expression increased after Ac2-26 treatment in neutrophils. Interestingly, the combination of Ac2-26 and cyclosporine A showed similar survival of transplants when compared with the cyclosporine A group, which could be attributed to a synergistic effect of both drugs. Investigations in vitro revealed that cyclosporine A inhibited extracellular-signal-regulated kinase (ERK) phosphorylation induced by Ac2-26 in neutrophils. Overall, the results suggest that AnxA1 has an essential role in augmenting the survival of skin allograft, mainly owing to inhibition of neutrophil transmigration and enhancement of apoptosis. This effect may lead to the development of new therapeutic approaches relevant to transplant rejection. Copyright (c) 2013 John Wiley & Sons, Ltd.
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    Hyperresponsiveness of neutrophils from gp 91(phox) deficient patients to lipopolysaccharide and serum amyloid A
    (Elsevier B.V., 2004-06-15) Hatanaka, E.; Carvalho, BTC; Condino-Neto, A.; Campa, A.; Universidade de São Paulo (USP); Universidade Federal de São Paulo (UNIFESP); Universidade Estadual de Campinas (UNICAMP)
    We demonstrate here that neutrophils from chronic granulomatous disease (CGD) patients release larger amounts of interleukin-8 (IL-8) and tumor necrosis factor alpha (TNF-alpha) than neutrophils from control subjects. Incremental cytokine production was observed under both basal and stimulated conditions in neutrophils from two CGD (gp 91(phox)) patients. the basal production of IL-8 was over seven-fold greater in CGD patients. the two samples assayed showed 3- and 10-fold increases in TNF-alpha. Basically, the same magnitude of increment was observed in lypopolysaccharide (LPS) and serum amyloid A protein (SAA)-stimulated cells. We also found that the levels of SAA and IL-8 were higher in the serum of CGD patients than the levels found in the serum of healthy donors. the increased responsiveness of neutrophils from CGD patients may be closely related with a deficiency in the assembly of the nicotinamide adenine dinucleotide phosphate (NADPH)-oxidase enzyme system, or it may be due to a frequent inflammatory condition in these patients. in the latter case, the increased serum levels of systemic inflammatory factors, among them SAA, would contribute to the sustained accumulation and activation of phagocytes. Whatever the origin, the excessive production of cytokines may lead to inappropriate activation and tissue injury and even to increased susceptibility to invasive microorganisms, impairing the quality life of CGD patients. (C) 2004 Elsevier B.V. All rights reserved.
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    Low density neutrophils in patients with juvenile idiopathic arthritis
    (Hogrefe & Huber Publishers, 2003-01-01) Ronchezel, M. V.; Hacbarth, E. T.; Len, Claudio Arnaldo [UNIFESP]; Terreri, Maria Teresa [UNIFESP]; Andrade, LEC [UNIFESP]; Hilário, Maria Odete Esteves [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Objectives: (1) To study the correlation among conventional clinical and laboratory parameters and the relation between the number of lymphocytes and neutrophils (L/N) in cell suspensions from peripheral blood of patients with juvenile idiopathic arthritis (JIA). (2) To evaluate the L/N relation of RA patients after an 8 year follow-up period. Methods: Fifty-one JIA patients (25 female, disease course: 19 systemic, 15 polyarticular, 17 pauciarticular) were enrolled in the study. To measure the L/N relation, we used Boyum's method: The leucocyte separation was done by centrifugation of peripheral blood on Ficoll-Hypaque (FH) gradient, and the number of lymphocytes, monocytes, and neutrophils in 500 cells was determined. The following clinical and laboratory parameters were evaluated: disease activity, number of active and limited joints, functional capacity, erythrocyte sedimentation rate (ESR), and C reactive protein (CRP). Twenty-four healthy children were used as controls. We also studied 13/51 patients from our Pediatric Rheumatology Unit who had been evaluated by the same method 8 years before. Results: We observed the lowest L/N relation in patients with active disease, especially those with polyarticular course. A statistical con-elation was also observed with the acute-phase reactants (ESR and CRP, p < 0.05). The majority of patients who had presented a low L/N relation at the first evaluation (8 years before) had a worse outcome. Conclusion: The measure of L/N relation from peripheral blood could be used as an auxiliary tool in the assessment of the activity and outcome of JIA patients, especially at disease onset.
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    Molecular studies reveal that A134T, G156A and G1333A SNPs in the CD177 gene are associated with atypical expression of human neutrophil antigen-2
    (Wiley-Blackwell, 2010-02-01) Moritz, E. [UNIFESP]; Chiba, A. K. [UNIFESP]; Kimura, E. Y. [UNIFESP]; Albuquerque, D.; Guirao, F. P. [UNIFESP]; Yamamoto, M. [UNIFESP]; Costa, F. F.; Bordin, J. O. [UNIFESP]; Universidade Federal de São Paulo (UNIFESP); Universidade Estadual de Campinas (UNICAMP)
    Background and ObjectivesThe human neutrophil antigen-2 (HNA-2) is expressed on a subpopulation of neutrophils as most subjects present a negative plus a positive HNA-2 population of neutrophils. the number of neutrophils expressing HNA-2 is variable and may increase in pregnancy, infections, myeloproliferative disorders and after G-CSF. This study investigated the presence of polymorphisms in the gene encoding HNA-2 (CD177) in individuals presenting different patterns of antigen expression and determined the association of single nucleotide polymorphisms (SNPs) with the heterogeneous HNA-2 expression.Materials and MethodsFlow cytometry was employed to analyse the HNA-2 expression on neutrophils from 135 healthy subjects using two monoclonal antibodies (TAG4, 7D8). Sequencing reactions were performed on subjects whose antigen expression was low (< 50%), high (>= 80%) or atypical (a nonreactive population plus two distinct positive cell populations).ResultsFive SNPs were detected, two of them (A793C, G1084A) were related to a low expression of HNA-2 (P = 0 center dot 031 and P = 0 center dot 004). Atypical antigen expression was observed in 5 center dot 9% (8/135) of the individuals, three nonpregnant women and five men. in these cases, the cDNA sequences revealed three SNPs (A134T, G156A and G1333A) strongly related to this atypical HNA-2 expression (P = 0 center dot 004, P = 0 center dot 006 and P < 0 center dot 0001, respectively).ConclusionsOur data show that polymorphisms in the CD177 are associated with variations in the HNA-2 expression and may be the cause of atypical expressions.
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    Neutrophils and the calcium-binding protein MRP-14 mediate carrageenan-induced antinociception in mice
    (Carfax Publishing, 2002-01-01) Pagano, R. L.; Dias, Maria Angela Amorim [UNIFESP]; Dale, C. S.; Giorgi, R.; Butantan Inst; Universidade Federal de São Paulo (UNIFESP)
    Background: We have previously shown that the calcium-binding protein MRP-14 secreted by neutrophils mediates the antinociceptive response in an acute inflammatory model induced by the intraperitoneal injection of glycogen in mice.Aim: in an attempt to broaden the concept that neutrophils and MRP-14 controls inflammatory pain induced by different type of irritants, in the present study, after demonstrating that carrageenan (Cg) also induces atinociception in mice, we investigated the participation of both neutrophils and MRP-14 in the phenomenon.Methods: Male Swiss mice were injected intraperitoneally with Cg and after different time intervals, the pattern of cell migration of the peritoneal exudate and the nociceptive response of animals submitted to the writhing test were evaluated. the participation of neutrophils and of the MRP-14 on the Cg effect was evaluated by systemic inoculation of monoclonal antibodies anti-granulocyte and anti-MRP-14.Results: Our results demonstrate that the acute neutrophilic peritonitis evoked by Cg induced antinociception 2, 4 and 8 h after inoculation of the irritant. Monoclonal antibodies anti-granulocyte or anti-MRP-14 reverts the antinociceptive response only 2 and 8 h after Cg injection. the antibody anti-MRP-14 partially reverts the antinociception observed after 4 h of Cg injection while the anti-granulocyte antibody enhances this effect. This effect is reverted by simultaneous treatment of the animals with both antibodies. After 4 h of Cg injection in neutrophil-depleted mice a significant expression of the calcium-binding protein MRP-14 was detected in the cytoplasm of peritoneal macrophages. This suggests that the enhancement of the effect observed after treatment with the anti-neutrophil antibody may be due to secretion of MRP-14 by macrophages. It has also been demonstrated that endogenous opioids and glucocorticoids are not involved in the antinociception observed at the 4th hour after Cg injection.Conclusion: These data support the hypothesis that neutrophils and the calcium-binding protein MRP-14 are participants of the endogenous control of inflammatory pain in mice despite the model of acute inflammation used.
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    Role of the bradykinin B-2 receptor for the local and systemic inflammatory response that follows severe reperfusion injury
    (Nature Publishing Group, 2003-05-01) Souza, Daniele G.; Pinho, Vanessa; Pesquero, Jorge L.; Lomez, Eliane S.; Poole, Steve; Juliano, Luiz [UNIFESP]; Correa Junior, Ary; Castro, M Salete D; Teixeira, Mauro M.; Universidade Federal de Minas Gerais (UFMG); Universidade Federal de São Paulo (UNIFESP); Natl Inst Biol Stand & Controls
    1 Bradykinin (BK) appears to play an important role in the development and maintenance of inflammation. Here, we assessed the role of the BK B-2 receptor for the injuries that occur after ischemia and reperfusion (I/R) of the territory irrigated by the superior mesenteric artery.2 Tissue (lung and duodenum) kallikrein activity increased after ischemia with greater enhancement after reperfusion. A selective inhibitor of tissue kallikrein, Phenylacetyl-Phe-Ser-Arg-N-(2,3-dinitrophenyl)-ethylenediamine (TKI, 0.001 - 10 mg ml(-1)), inhibited kallikrein activity in a concentration-dependent manner in vitro. in vivo, pretreatment with TKI (30 mg kg(-1)) prevented the extravasation of plasma and the recruitment of neutrophils.3 Similarly, the bradykinin B-2 receptor antagonists, HOE 140 (0.01-1.0 mg kg(-1)) or FR173657 (10.0 mg kg(-1)), inhibited reperfusion-induced increases in vascular permeability and the recruitment of neutrophils in the intestine and lungs.4 in a model of more severe I/R injury, HOE 140 (1.0mg kg(-1)) inhibited the increase in vascular permeability, neutrophil recruitment, haemorrhage and tissue pathology. Furthermore, HOE 140 significantly inhibited the elevations of TNF-alpha in tissue and serum and partially prevented lethality. This was associated with an increase in the concentrations of IL-10 in tissue and serum.5 Thus, our results demonstrate that, following intestinal I/R injury, there is an increase in tissue kallikrein activity and activation of BK B-2 receptors. B-2 receptor activation is essential for the development of inflammatory tissue injury and lethality. These results contrast with those of others showing that BK mostly exerts a protective role during I/R injury.
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    TLR signaling pathway in patients with sepsis
    (Lippincott Williams & Wilkins, 2008-01-01) Salomao, Reinaldo [UNIFESP]; Martins, Paulo Sergio [UNIFESP]; Brunialti, Milena Karina Coló [UNIFESP]; Fernandes, Maria da Luz [UNIFESP]; Martos, Leandro Silva Willish [UNIFESP]; Mendes, Marialice Erdelyi [UNIFESP]; Gomes, Natalia E. [UNIFESP]; Rigato, Otelo [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    The pathogenesis of sepsis involves complex interaction between the host and the infecting microorganism. Bacterial recognition and signaling are essential functions of the cells of innate immune systems and drive a coordinated immune response. One of the more intriguing aspects of sepsis is the fact that the protective and damaging host response are part of the same process, that is, the inflammatory response that is aimed to control the infectious process also underscores many of the pathophysiological events of sepsis. the discovery of Toll-like receptors (TLRs) in humans, and the early recognition of TLR-4 as the receptor that signals LPS bioactivity were major breakthroughs not only in the field of sepsis but also in immunology as a whole. in this article, we aimed to review TLR expression and signaling in the context of sepsis. the results obtained by our group show that TLR and other cellular surface receptors may be differently regulated on mononuclear cells and neutrophils, and that they are dynamically modulated across the stages of sepsis. Toll-like receptor signaling gene expression in mononuclear cells is decreased in more severe forms of the disease. in contrast, up-regulated genes are seen along the clinical spectrum of sepsis in neutrophils.
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    Toll-like receptor pathway signaling is differently regulated in neutrophils and peripheral mononuclear cells of patients with sepsis, severe sepsis, and septic shock
    (Lippincott Williams & Wilkins, 2009-01-01) Salomao, Reinaldo [UNIFESP]; Brunialti, Milena K. C. [UNIFESP]; Gomes, Natalia E. [UNIFESP]; Mendes, Marialice E. [UNIFESP]; Diaz, Ricardo Sobhie [UNIFESP]; Komninakis, Shirley [UNIFESP]; Machado, Flavia R. [UNIFESP]; Silva, Ismael Dale Cotrim Guerreiro da [UNIFESP]; Rigato, Otelo [UNIFESP]; Universidade Federal de São Paulo (UNIFESP)
    Objectives: Up- and down-regulation of inflammatory response was described in blood cells from septic patients, according to the stage of sepsis and the cells evaluated. This study aimed to evaluate the Toll-like receptor (TLR) signaling pathway gene expression in peripheral blood mononuclear cells (PBMC) and neutrophils in patients throughout the different stages of sepsis.Design: Prospective, observational study.Settings. Two emergency rooms and two intensive care units in one university and one teaching hospital.Patients and Controls., A total of 15 septic patients, five with sepsis, five with severe sepsis, and five with septic shock, in addition to five healthy volunteers were enrolled.Interventions: None.Measurements and Main Results: the Human-TLR Signaling Pathway, which comprises 84 genes related to TLR-mediated signal transduction, was evaluated by real time polymerase chain reaction in PBMC and neutrophils obtained from patients and controls. the fold change for each gene (2((-Delta Delta Ct))) was compared between the groups. Genes with fold changes greater than 2 and significant changes in Delta CT are reported as differently expressed. the told change ratios in PBMC gene expression between septic patients and healthy controls revealed a dynamic process according to the stage of sepsis, tending toward down-regulation of the TLR signaling pathway in PBMC in the more severe forms of the disease. However, the differential gene expression was restricted to five down-regulated genes in septic shock patients, which are found in the effector and downstream pathways. Neutrophils showed a different pattern of adaptation. Patients with sepsis, severe sepsis, and septic shock presented a broad gene upregulation, which included all functional groups evaluated and persisted throughout the stages of the disease.Conclusions: TLR-signaling pathway genes are differently regulated in PBMC and neutrophils of septic patients, and are dynamically modulated throughout the different stages of sepsis. (Grit Care Med 2009; 37:132-139)