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Since the pandemic's onset, a growing population of individuals has recovered from SARS-CoV-2 infection and its long-term effects in some of the convalescents are gradually being reported. Although the precise etiopathogenesis of post-acute COVID-19 sequelae (PACS) remains elusive, the mainly accepted rationale is that SARS-CoV-2 exerts long-lasting immunomodulatory effects, promotes chronic low-grade inflammation, and causes irreversible tissue damage. So far, several viruses have been causally linked to human oncogenesis, whereas chronic inflammation and immune escape are thought to be the leading oncogenic mechanisms. Excessive cytokine release, impaired T-cell responses, aberrant activation of regulatory signaling pathways (e.g., JAK-STAT, MAPK, NF-kB), and tissue damage, hallmarks of COVID-19 disease course, are also present in the tumor microenvironment. Therefore, the intersection of COVID-19 and cancer is partially recognized and the long-term effects of the virus on oncogenesis and cancer progression have not been explored yet. Herein, we present an up-to-date review of the current literature regarding COVID-19 and cancer cross-talk, as well as the oncogenic pathways stimulated by SARS-CoV-2.
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OBJECTIVE: The clinical profile, management and outcome of infective endocarditis (IE) may be influenced by socioeconomic issues. METHODS: A nationwide prospective study evaluated IE during the era of deep economic crisis in Greece. Epidemiological data and factors associated with 60-day mortality were analyzed through descriptive statistics, logistic and Cox-regression models. RESULTS: Among 224 patients (male 72.3%, mean age 62.4 years), Staphylococcus aureus (n = 62; methicillin-resistant S. aureus (MRSA) 33.8%) predominated in the young without impact on mortality (p = 0.593), whilst Enterococci (n = 36) predominated in the elderly. Complications of IE were associated with mortality: heart failure [OR 2.415 (95% CI: 1.159-5.029), p = 0.019], stroke [OR 3.206 (95% CI: 1.190-8.632), p = 0.018] and acute kidney injury [OR 2.283 (95% CI: 1.085-4.805), p = 0.029]. A 60-day survival benefit was solely related to cardiac surgery for IE during hospitalization [HR 0.386 (95% CI: 0.165-0.903), p = 0.028] and compliance with antimicrobial treatment guidelines [HR 0.487 (95% CI: 0.259-0.916), p = 0.026]. Compared with a previous country cohort study, history of rheumatic fever and native valve predisposition had declined, whilst underlying renal disease and right-sided IE had increased (p < 0.0001); HIV infection had emerged (p = 0.002). No difference in rates of surgery and outcome was assessed. CONCLUSIONS: A country-wide survey of IE highlighted emergence of HIV, right-sided IE and predominance of MRSA in the youth during a severe socioeconomic crisis. Compliance with treatment guidelines promoted survival.
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Endocardite/epidemiologia , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Estudos de Coortes , Endocardite/microbiologia , Endocardite/mortalidade , Endocardite/virologia , Grécia/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
BACKGROUND: Failure of circulating monocytes for adequate cytokine production is a trait of sepsis-induced immunosuppression; however, its duration and association with final outcome are poorly understood. METHODS: We conducted a substudy of a large randomised clinical trial. Peripheral blood mononuclear cells (PBMCs) were isolated within the first 24 h from the onset of systemic inflammatory response syndrome in 95 patients with microbiologically confirmed or clinically suspected gram-negative infections. Isolation was repeated on days 3, 7 and 10. PBMCs were stimulated for cytokine production. The study endpoints were the differences between survivors and non-survivors, the persistence of immunosuppression, and determination of admission clinical signs that can lead to early identification of the likelihood of immunosuppression. RESULTS: PBMCs of survivors produced significantly greater concentrations of tumour necrosis factor-α (TNF-α), interleukin (IL)-6, IL-8, IL-10, interferon-γ and granulocyte-macrophage colony-stimulating factor after day 3. Using ROC analysis, we found that TNF-α production less than 250 pg/ml after lipopolysaccharide stimulation on day 3 could discriminate patients from healthy control subjects; this was associated with a 5.18 OR of having an unfavourable outcome (p = 0.046). This trait persisted as long as day 10. Logistic regression analysis showed that cardiovascular failure on admission was the only independent predictor of defective TNF-α production on day 3. CONCLUSIONS: Defective TNF-α production is a major trait of sepsis-induced immunosuppression. It is associated with significant risk for unfavourable outcome and persists until day 10. Cardiovascular failure on admission is predictive of defective TNF-α production during follow-up. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01223690 . Registered on 18 October 2010.
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Bactérias Gram-Negativas/metabolismo , Infecções/complicações , Leucócitos Mononucleares/classificação , Idoso , Idoso de 80 Anos ou mais , Claritromicina/farmacologia , Claritromicina/uso terapêutico , Técnicas de Apoio para a Decisão , Feminino , Bactérias Gram-Negativas/patogenicidade , Fator Estimulador de Colônias de Granulócitos e Macrófagos/análise , Fator Estimulador de Colônias de Granulócitos e Macrófagos/sangue , Grécia , Humanos , Infecções/sangue , Interferon gama/análise , Interferon gama/sangue , Interleucina-10/análise , Interleucina-10/sangue , Interleucina-6/análise , Interleucina-6/sangue , Interleucina-8/análise , Interleucina-8/sangue , Leucócitos Mononucleares/patologia , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Placebos , Estudos Prospectivos , Curva ROC , Proteínas Recombinantes/análise , Proteínas Recombinantes/sangue , Estatísticas não Paramétricas , Sobreviventes/estatística & dados numéricos , Fator de Necrose Tumoral alfa/análise , Fator de Necrose Tumoral alfa/sangueRESUMO
Acute pyelonephritis is an infection of the renal parenchyma and renal pelvis. When it is caused by a typical pathogen in an immunocompetent female patient with normal urinary tract, it is considered uncomplicated. In all other cases, sepsis is the most worrisome complication. In the event of sepsis, patients should be hospitalized and treated aggressively with antibiotics, intravenous fluids and agents that enhance the immune response of the host. In this review, we summarize findings from immunomodulatory interventions in experimental studies of acute pyelonephritis and the application of these interventions into clinical practice. Vaccine against bacterial virulence factors and agents aiming to modulate the immune response of the host belong to these interventions and they are discussed.
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Imunomodulação/efeitos dos fármacos , Imunoterapia , Pielonefrite/terapia , Doença Aguda , Feminino , Humanos , Imunoterapia/métodos , Pielonefrite/complicações , Pielonefrite/imunologia , Sepse/etiologia , Sepse/terapia , Infecções Urinárias/etiologia , Infecções Urinárias/terapia , Fatores de Virulência/antagonistas & inibidores , Fatores de Virulência/imunologiaRESUMO
BACKGROUND: Based on previous animal studies showing promising immunomodulatory efficacy esmolol, a selective ß1-blocker, it was assumed that administration of esmolol in experimental pyelonephritis by multidrug-resistant Pseudomonas aeruginosa would prolong survival and modulate immune response. METHODS: Acute pyelonephritis was induced in 80 rabbits and assigned to eight groups receiving normal saline (controls), esmolol, amikacin, or both agents as pretreatment and as treatment. Blood was sampled for measurement of malondialdehyde and tumor necrosis factor alpha. Animals were followed up for survival, and after death quantitative tissue cultures were performed. The in vitro effect of esmolol on bacterial growth and on the oxidative burst of neutrophils of healthy controls and of sepsis patients was studied. RESULTS: Survival of pretreatment groups administered single esmolol or esmolol and amikacin was prolonged compared with that of controls (P = 0.018 and P = 0.014, respectively); likewise, survival of treatment groups administered single esmolol or both agents was prolonged compared with that of controls (P = 0.007 and P = 0.014, respectively). Circulating malondialdehyde was significantly lower in pretreated animals administered esmolol or esmolol and amikacin compared with that in controls and in treated animals administered both agents compared with in controls (P = 0.020). In these groups, the bacterial load of the lung was significantly lower compared with controls. Serum tumor necrosis factor alpha did not change. Amikacin was increased in serum of esmolol-treated animals at levels which inhibited the in vitro growth of the studied isolate. Esmolol did not modify the in vitro growth of P aeruginosa and the oxidative burst of neutrophils. CONCLUSIONS: It is concluded that esmolol prolonged survival after experimental infection by multidrug-resistant P aeruginosa. Survival benefit may be related with pleiotropic actions connected with modulation of pharmacokinetics and attenuation of inflammation.
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Antagonistas de Receptores Adrenérgicos beta 1/uso terapêutico , Fatores Imunológicos/uso terapêutico , Propanolaminas/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Pielonefrite/tratamento farmacológico , Animais , Farmacorresistência Bacteriana Múltipla , Feminino , Humanos , Masculino , Malondialdeído/sangue , Infecções por Pseudomonas/mortalidade , Pseudomonas aeruginosa/efeitos dos fármacos , Pielonefrite/mortalidade , CoelhosRESUMO
The exact time frame of multiple trauma-induced immunosuppression and the immune mechanisms mediating transition to severe sepsis are largely unknown. Peripheral blood mononuclear cells were isolated from 69 patients with multiple injuries within the first 24h from injury and from 36 healthy volunteers and stimulated for cytokine production. Circulating endotoxins were measured by the kinetic LAL assay. Measurements were repeated the first 24h of sepsis onset. Patients had defective responses for tumour necrosis factor-alpha (TNFα), interleukin (IL)-10, IL-17 and interferon-gamma (IFNγ) using a broad-panel of bacterial stimuli. Production of IFNγ was pronounced for patients with trauma-related multiple organ failure (MOF). Thirty-six patients developed severe sepsis. At that time, production of TNFα was increased compared to baseline. The increase was greater among non-survivors than among survivors. Enhanced TNFα production on sepsis onset was a main finding of patients without endotoxemia. Immunosuppression of both innate and adaptive cytokine responses appears as early as the first 24h from injury. Transition into severe sepsis due to bacterial superinfection is accompanied by enhanced production of TNFα and this is linked with unfavorable outcome.
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Citocinas/biossíntese , Leucócitos Mononucleares/imunologia , Traumatismo Múltiplo/imunologia , Sepse/imunologia , Fator de Necrose Tumoral alfa/biossíntese , Adulto , Translocação Bacteriana , Células Cultivadas , Citocinas/sangue , Endotoxemia/imunologia , Feminino , Humanos , Imunidade Inata , Interferon gama/biossíntese , Interferon gama/sangue , Interferon gama/imunologia , Interleucina-10/biossíntese , Interleucina-10/sangue , Interleucina-10/imunologia , Interleucina-17/biossíntese , Interleucina-17/sangue , Interleucina-17/imunologia , Interleucina-6/biossíntese , Interleucina-6/sangue , Interleucina-6/imunologia , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/imunologia , Sepse/fisiopatologia , Fator de Necrose Tumoral alfa/sangue , Fator de Necrose Tumoral alfa/imunologiaRESUMO
One prospective, open-label, non-randomized study was conducted in 100 patients to define the antipyretic and analgesic effect of a new intravenous formulation of 1 g of paracetamol; 71 received paracetamol for the management of fever and 29 received paracetamol for pain relief after abdominal surgery or for neoplastic pain. Serial follow-up measurements of core temperature and of pain intensity were done for 6 h. Additional rescue medications were recorded for 5 days. Blood was sampled for the measurement of free paracetamol (APAP) and of glucuronide-APAP and N-sulfate-APAP by an HPLC assay. Defervescence, defined as core temperature below or equal to 37.1°C, was achieved in 52 patients (73.2%) within a median time of 3 h. Patients failing to become afebrile with the first dose of paracetamol became afebrile when administered other agents as rescue medications. Analgesia was achieved in 25 patients (86.4%) within a median time of 2 h. Serum levels of glucuronide-APAP were greater among non-responders to paracetamol. The presented results suggest that the intravenous formulation of paracetamol is clinically effective depending on drug metabolism.
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Dor Abdominal/tratamento farmacológico , Acetaminofen/administração & dosagem , Acetaminofen/metabolismo , Febre/tratamento farmacológico , Dor Intratável/tratamento farmacológico , Dor Pós-Operatória/tratamento farmacológico , Acetaminofen/sangue , Acetaminofen/farmacocinética , Adolescente , Adulto , Idoso , Feminino , Febre/etiologia , Humanos , Infecções/complicações , Infusões Intravenosas , Interleucina-6/sangue , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do Tratamento , Adulto JovemRESUMO
Evidence from a recent randomized study of our group suggests that intravenous clarithromycin resulted in earlier resolution of ventilator-associated pneumonia. The need to understand the mechanism of action of clarithromycin guided to the study of a model of experimental empyema by multidrug-resistant Pseudomonas aeruginosa in 40 rabbits. Animals were randomized into controls (group A); treatment with clarithromycin (group B); treatment with piperacillin/tazobactam (group C); and treatment with both agents (group D). Pleural fluid was collected at regular time intervals for quantitative culture, estimation of cell apoptosis and of concentrations of tumour necrosis factor-alpha (TNFα). After 7 days, animals were euthanized for estimation of tissue growth. Bacterial growth in the pleural fluid of group D was significantly decreased compared with the other groups on day 5. Lung growth of group D was lower than group A. That was also the case of cytokine stimulation by pleural fluid samples on U937 monocytes. It is concluded that administration of clarithromycin enhanced the antimicrobial efficacy of piperacillin/tazobactam and decreased bacterial growth in the pleural fluid and in tissues. It also attenuated the pro-inflammatory phenomena induced by the ß-lactam.
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Antibacterianos/uso terapêutico , Claritromicina/uso terapêutico , Empiema Pleural/tratamento farmacológico , Empiema Pleural/microbiologia , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/uso terapêutico , Animais , Antibacterianos/administração & dosagem , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Claritromicina/administração & dosagem , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla , Quimioterapia Combinada , Empiema Pleural/imunologia , Humanos , Interleucina-6/biossíntese , Masculino , Ácido Penicilânico/administração & dosagem , Ácido Penicilânico/análogos & derivados , Piperacilina/administração & dosagem , Combinação Piperacilina e Tazobactam , Derrame Pleural/imunologia , Derrame Pleural/microbiologia , Infecções por Pseudomonas/imunologia , Pseudomonas aeruginosa/efeitos dos fármacos , Coelhos , Fator de Necrose Tumoral alfa/biossíntese , Células U937RESUMO
BACKGROUND: This study was conducted to investigate the effects of intravenous thalidomide administration in an experimental model of musculoskeletal trauma. We hypothesized that because thalidomide inhibits secretion of tumor necrosis factor alpha (TNF-α), survival of animals that received thalidomide would be significantly prolonged. MATERIAL AND METHODS: After an open fracture of the right femur, 24 rabbits were randomly assigned to control and thalidomide groups. Intravenous therapy with thalidomide was started 30 min after fracture. Hemodynamic monitoring of all animals was performed for 4 h. Survival was recorded and bacterial growth in blood and organs was measured after animal death or sacrifice. Blood was sampled for TNF-α measurement and for isolation of peripheral blood mononuclear cells (PBMCs). Apoptosis of PBMCs was measured by flow cytometry. RESULTS: Survival was significantly prolonged in the thalidomide group. Apoptosis of PBMCs was increased in the control group compared with the thalidomide group at 24 h. There were no differences in vital signs, blood and tissue cultures, and serum TNF-α concentration between the two groups. CONCLUSIONS: Intravenous thalidomide prolonged survival in an experimental model of severe musculoskeletal injury in rabbits. Its mechanism of action did not involve TNF-α suppression but prevention of mononuclear apoptosis. In view of these promising results, further research is needed to clarify the immunomodulatory mechanism of action of thalidomide and its potential use for the management of severe trauma.
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Apoptose/efeitos dos fármacos , Fraturas do Fêmur/complicações , Fraturas Expostas/complicações , Imunossupressores/uso terapêutico , Síndrome de Resposta Inflamatória Sistêmica/prevenção & controle , Talidomida/uso terapêutico , Animais , Avaliação Pré-Clínica de Medicamentos , Imunossupressores/farmacologia , Infusões Intravenosas , Masculino , Coelhos , Distribuição Aleatória , Síndrome de Resposta Inflamatória Sistêmica/etiologia , Talidomida/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidoresRESUMO
OBJECTIVE: An experimental model of severe injury with great lethality was studied to define the impact of bacterial translocation on survival and on inflammatory response. METHODS: Forty-one rabbits were divided into two groups: A, femur myotomy; and B, myotomy and fracture of the femoral bone. Vital signs and survival were recorded. Serum circulating endotoxins (lipopolysaccharides; LPS) were determined and tissue cultures were performed at necropsy. A subgroup of animals was sacrificed at 48 h post injury; LPS was determined in abdominal aorta and portal vein, apoptosis of spleen cells was assessed by flow cytometry, and ex vivo production of tumor necrosis factor alpha by splenocytes was measured. RESULTS: Tissue bacterial burden was increased in animals that died early (i.e., within 48 h after injury) versus rabbits that died later. Portal vein LPS at 48 h was increased in group B compared with group A, whereas circulating LPS did not differ. No difference in apoptosis of either lymphocytes or macrophages of the spleen was found in group B compared with group A. Following stimulation with LPS or phytohemagglutinin, tumor necrosis factor α production by splenocytes of group B was greater than that of group A. CONCLUSIONS: Bacterial translocation primes enhanced proinflammatory responses and it is associated with early death in severe trauma.
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Translocação Bacteriana/imunologia , Fraturas do Fêmur , Inflamação , Índices de Gravidade do Trauma , Animais , Aorta Abdominal , Modelos Animais de Doenças , Fraturas do Fêmur/imunologia , Fraturas do Fêmur/microbiologia , Fraturas do Fêmur/mortalidade , Inflamação/imunologia , Inflamação/microbiologia , Inflamação/mortalidade , Lipopolissacarídeos/toxicidade , Masculino , Veia Porta , Coelhos , Baço/imunologia , Baço/metabolismo , Fator de Necrose Tumoral alfa/sangueRESUMO
INTRODUCTION: Recent evidence suggests a link between excess lipid peroxidation and specific organ failures in sepsis. No study has been performed in sepsis by multidrug-resistant (MDR) Gram-negative bacteria. METHODS: Lethal sepsis was induced in rats by the intraperitoneal injection of one MDR isolate of Pseudomonas aeruginosa. Produced malondialdehyde (MDA) was measured in tissues 5 hours after bacterial challenge with the thiobarbiturate assay followed by high-performance liquid chromatography (HPLC) analysis. Results were compared with those from a cohort of patients with ventilator-associated pneumonia (VAP) and sepsis by MDR Gram-negative bacteria. More precisely, serum MDA was measured on 7 consecutive days, and it was correlated with clinical characteristics. RESULTS: MDA of septic rats was greater in the liver, spleen, and aortic wall, and it was lower in the right kidney compared with sham operated-on animals. Findings were confirmed by the studied cohort. Circulating MDA was greater in patients with hepatic dysfunction and acute respiratory distress syndrome (ARDS) compared with patients without any organ failures. The opposite was found for patients with acute renal dysfunction. No differences were found between patients with ARDS without or with cardiovascular (CV) failure and patients without any organ failure. Serial measurements of MDA in serum of patients indicated that levels of MDA were greater in survivors of hepatic dysfunction and ARDS and lower in survivors of acute renal dysfunction. CONCLUSIONS: Animal findings and results of human sepsis are complementary, and they suggest a compartmentalization of lipid peroxidation in systemic infections by MDR gram-negative bacteria.
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Farmacorresistência Bacteriana Múltipla/fisiologia , Bactérias Gram-Negativas/metabolismo , Peroxidação de Lipídeos/fisiologia , Sepse/sangue , Sepse/diagnóstico , Animais , Estudos de Coortes , Método Duplo-Cego , Seguimentos , Humanos , Masculino , Malondialdeído/sangue , Pseudomonas aeruginosa/metabolismo , Ratos , Ratos Wistar , Fator de Necrose Tumoral alfa/sangueRESUMO
The present study focused on the impact of methicillin resistance of Staphylococcus aureus on cytokine production by monocytes. Cytokine stimulation was studied by 20 heat-killed isolates, 10 methicillin-susceptible Staphylococcus aureus (MSSA) and 10 methicillin-resistant Staphylococcus aureus (MRSA). Bacterial endocarditis was induced in 27 male rabbits by challenge with 1 MSSA isolate and 1 MRSA isolate. Blood was sampled for estimation of tumor necrosis factor-alpha (TNF-α) and malondialdehyde (MDA) and stimulation of monocytes. MSSA induced greater stimulation of TNF-α than MRSA, as shown after addition of a Toll-like receptor-4 (TLR4) antagonist. Survival of rabbits challenged by MRSA was prolonged compared to those challenged by MSSA. Serum MDA was greater after MSSA stimulation. Serum of animals challenged by MRSA stimulated greater release of interleukin (IL)-8 and IL-10 compared with MSSA: the opposite was observed for TNF-α. It is concluded that MSSA and MRSA induce a different pattern of TNF-α stimulation through a TLR4-independent mechanism, leading to shorter survival in experimental endocarditis.
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Citocinas/imunologia , Endocardite Bacteriana/imunologia , Endocardite Bacteriana/metabolismo , Staphylococcus aureus Resistente à Meticilina/imunologia , Staphylococcus aureus/imunologia , Animais , Linhagem Celular , Citocinas/sangue , Citocinas/metabolismo , Endocardite Bacteriana/sangue , Endocardite Bacteriana/microbiologia , Interações Hospedeiro-Patógeno , Humanos , Estimativa de Kaplan-Meier , Masculino , Malondialdeído/sangue , Malondialdeído/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , CoelhosRESUMO
Levels of circulating angiopoietin-2 (Ang-2) increase in sepsis, raising the possibility that Ang-2 acts as a modulator in the sepsis cascade. To investigate this, experimental sepsis was induced in male C57BL6 mice by a multidrug-resistant isolate of Pseudomonas aeruginosa; survival was determined along with neutrophil tissue infiltration and release of proinflammatory cytokines. Survival was significantly increased either by pretreatment with recombinant Ang-2 2 h before or treatment with recombinant Ang-2 30 min after bacterial challenge. Likewise, Ang-2 pretreatment protected against sepsis-related death elicited by Escherichia coli; however, Ang-2 failed to provide protection in lipopolysaccharide (LPS)-challenged mice. The survival advantage of Ang-2 in response to P. aeruginosa challenge was lost in tumor necrosis factor (TNF)-deficient mice or neutropenic mice. Infiltration of the liver by neutrophils was elevated in the Ang-2 group compared with saline-treated animals. Serum TNF-α levels were reduced by Ang-2, whereas those of interleukin (IL)-6 and IL-10 remained unchanged. This was accompanied by lower release of TNF-α by stimulated splenocytes. When applied to U937 cells in vitro, heat-killed P. aeruginosa induced the secretion of IL-6 and TNF-α; low levels of exogenous TNF-α synergized with P. aeruginosa. This synergistic effect was abolished after the addition of Ang-2. These results put in evidence a striking protective role of Ang-2 in experimental sepsis evoked by a multidrug-resistant isolate of P. aeruginosa attributed to modulation of TNF-α production and changes in neutrophil migration. The protective role of Ang-2 is shown when whole microorganisms are used and not LPS, suggesting complex interactions with the host immune response.
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Angiopoietina-2/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Sepse/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Permeabilidade Capilar/efeitos dos fármacos , Contagem de Células , Ensaio de Unidades Formadoras de Colônias , Citocinas/biossíntese , Farmacorresistência Bacteriana Múltipla , Escherichia coli/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neutrófilos/efeitos dos fármacos , Cavidade Peritoneal/citologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/patologia , Pseudomonas aeruginosa/patogenicidade , Sepse/microbiologia , Sepse/patologia , Baço/citologia , Baço/metabolismo , Análise de Sobrevida , Fator de Necrose Tumoral alfa/genética , Células U937RESUMO
One recent, double-blind, randomized clinical trial with 200 patients showed that clarithromycin administered intravenously for 3 days in patients with ventilator-associated pneumonia (VAP) accelerated the resolution of pneumonia and decreased the risk of death from septic shock and multiple organ dysfunctions (MODS). The present study focused on the effect of clarithromycin on markers of inflammation in these patients. Blood was drawn immediately before the administration of the allocated treatment and on six consecutive days after the start of treatment. The concentrations of circulating markers were measured. Monocytes and neutrophils were isolated for immunophenotyping analysis and for cytokine stimulation. The ratio of serum interleukin-10 (IL-10) to serum tumor necrosis factor alpha (TNF-α) was decreased in the clarithromycin group compared with the results in the placebo group. Apoptosis of monocytes was significantly increased on day 4 in the clarithromycin group compared with the rate of apoptosis in the placebo group. On the same day, the expression of CD86 was increased and the ratio of soluble CD40 ligand (sCD40L) to CD86 in serum was unchanged. The release of TNF-α, IL-6, and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) by circulating monocytes after stimulation was greater in the clarithromycin group than in the placebo group. The expression of TREM-1 on monocytes was also increased in the former group. These effects were pronounced in patients with septic shock and MODS. These results suggest that the administration of clarithromycin restored the balance between proinflammatory versus anti-inflammatory mediators in patients with sepsis; this was accompanied by more efficient antigen presentation and increased apoptosis. These effects render new perspectives for the immunotherapy of sepsis.
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Claritromicina/uso terapêutico , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/patogenicidade , Pneumonia Associada à Ventilação Mecânica/sangue , Pneumonia Associada à Ventilação Mecânica/tratamento farmacológico , Sepse/sangue , Sepse/tratamento farmacológico , Apoptose/efeitos dos fármacos , Antígeno B7-2/sangue , Ligante de CD40/sangue , Método Duplo-Cego , Humanos , Interleucina-10/sangue , Interleucina-6/sangue , Fator de Necrose Tumoral alfa/sangueRESUMO
OBJECTIVES: To identify the role of single nucleotide polymorphisms (SNPs) of the tumor necrosis factor (TNF) gene in the natural course of 2009 influenza A H1N1 virus infection. METHODS: Genomic DNA was isolated from 109 patients with an H1N1 infection and from 108 healthy volunteers. SNPs of the TNF gene were assessed after electrophoresis of the digested PCR products by restriction enzymes. RESULTS: The frequency of the -238 A allele was significantly greater among patients than among controls. Viral pneumonia developed in 20 of 96 non-carriers of at least one -238 A allele (20.8%) and in seven of 13 carriers of at least one -238 A allele (53.8%, p=0.016). Logistic regression analysis showed that the most important factors associated with the development of pneumonia were the presence of an underlying disease (p=0.021, odds ratio (OR) 3.08) and the carriage of at least one -238 A allele (p=0.041, OR 3.74). Gene transcripts of the TNF gene were greater among non-carriers of the -238 A allele than among carriers of the -238 A allele. CONCLUSIONS: The -238 A SNP allele of the TNF gene imposes on the course of 2009 H1N1 virus infection and is an independent risk factor for pneumonia.
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Influenza Humana/epidemiologia , Influenza Humana/genética , Leucócitos Mononucleares/virologia , Polimorfismo de Nucleotídeo Único , Fator de Necrose Tumoral alfa/genética , Alelos , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Vírus da Influenza A Subtipo H1N1/patogenicidade , Influenza Humana/virologia , Leucócitos Mononucleares/metabolismo , Modelos Logísticos , Masculino , Fatores de RiscoRESUMO
Severe trauma induces systemic inflammatory response syndrome (SIRS) through the release of proinflammatory mediators. Angiopoietin-2 (Ang-2) is over-produced in sepsis and leads to dysfunction of endothelial cells and subsequent multiple organ dysfunction. In order to define the role of Ang-2 in lethal injury, 45 rabbits were studied; eight were administered anesthesia; 11 were sham-operated and 26 were subject to femoral injury. Concentrations of Ang-2, malondialdehyde (MDA), tumor necrosis factor-alpha (TNFα) and endotoxins (LPS) were determined in serum and of Ang-2 in tissues; vital signs and overall survival were recorded. Bacterial growth was quantitatively assessed in liver, spleen and lung of animal that died. Survival of injured animals was shorter than sham operated ones. Serum concentrations of Ang-2 at 4 h was greater among animals where death supervened early, i.e. within 48 h after injury than among rabbits that died later. That was also the case for systolic, diastolic and mean arterial pressures. Serum MDA and TNFα and tissue bacterial growth did not differ between rabbits that died early and rabbits that died late. Serum LPS remained below the limit of detection. These results suggest that circulating Ang-2 participates in the pathogenesis of SIRS after injury connected with early haemodynamic instability.
Assuntos
Angiopoietina-2/sangue , Morte , Progressão da Doença , Fêmur/lesões , Fêmur/patologia , Anestesia , Animais , Pressão Sanguínea , Diástole , Fêmur/fisiopatologia , Masculino , Malondialdeído/sangue , Coelhos , Análise de Sobrevida , Sístole , Fator de Necrose Tumoral alfa/sangueRESUMO
CONTEXT: Soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) participates in the inflammatory process. PURPOSE: To describe changes of sTREM-1 in the serum after hemiarthroplasty (HA) and total hip arthroplasty (THA). METHODS: Serial blood samples were drawn from 122 patients with hip fracture. Interleukin-6 (IL-6), sTREM-1, and C-reactive protein (CRP) were measured. RESULTS: IL-6 and CRP were similarly increased after both HA and THA. sTREM-1 was increased early in HA and late after THA. The only parameter that was higher among patients who developed systemic inflammatory response syndrome was IL-6. CONCLUSIONS: Kinetics of sTREM-1 differs among patients undergoing HA of the hip and those undergoing THA.
Assuntos
Artroplastia/métodos , Fraturas do Quadril/sangue , Fraturas do Quadril/cirurgia , Glicoproteínas de Membrana/sangue , Receptores Imunológicos/sangue , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , Feminino , Humanos , Técnicas Imunoenzimáticas , Interleucina-6/sangue , Cinética , Masculino , Receptor Gatilho 1 Expresso em Células MieloidesRESUMO
BACKGROUND: Pseudomonas aeruginosa is a cause of infections of the lower respiratory tract among patients with chronic lung disorders. It is questionable whether virulence of this species may be influenced by multidrug resistance (MDR). OBJECTIVES: To define the impact of MDR in experimental lung infection. METHODS: Experimental empyema was induced in rabbits by MDR (group A, n = 16) and by susceptible isolates (group B, n = 10). Pleural fluid was sampled for quantitative culture and estimation of cell apoptosis and of tumor necrosis factor-alpha (TNFα) and malondialdehyde (MDA). Survival was recorded. Cytokine production was stimulated in U937 monocytes by samples of pleural fluid. Whole blood of rabbits was incubated with the isolates; induction of apoptosis was assessed. RESULTS: Survival of group A was prolonged compared to group B. This was accompanied by lower bacterial counts of the inoculated pathogens in pleural fluid and in the lungs of group A compared with group B. Early apoptosis of neutrophils of pleural fluid of group A was lower compared with group B. Pleural fluid concentrations of TNFα and MDA did not differ between the groups. Cytokine production by U937 monocytes after stimulation with pleural fluid was greater in group B than in group A. The susceptible isolate induced apoptosis of neutrophils in vitro at a greater rate than the MDR isolate. CONCLUSIONS: Experimental empyema by susceptible P. aeruginosa is accompanied by greater mortality compared with MDR P. aeruginosa. This phenomenon may be attributed to the different growth pattern of the pathogens or to their interaction with the innate immune system.
Assuntos
Farmacorresistência Bacteriana Múltipla , Empiema/microbiologia , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/fisiologia , Animais , Carga Bacteriana , Citocinas/biossíntese , Suscetibilidade a Doenças , Farmacorresistência Bacteriana Múltipla/fisiologia , Empiema/mortalidade , Humanos , Imunidade Inata/fisiologia , Pulmão/microbiologia , Masculino , Malondialdeído/metabolismo , Monócitos/metabolismo , Neutrófilos , Derrame Pleural/patologia , Derrame Pleural/fisiopatologia , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pseudomonas aeruginosa/patogenicidade , Coelhos , Especificidade da Espécie , Taxa de Sobrevida , Fator de Necrose Tumoral alfa/metabolismo , Células U937/metabolismo , Virulência/fisiologiaRESUMO
In an attempt to define the efficacy of intravenously administered n-3 polyunsaturated fatty acids (PUFAs) in an animal model of lethal trauma following femur fracture, an intravenous solution of eicosapentanoic acid (EPA) - one n-3 PUFA - was administered in 25 rabbits; 13 were controls and 12 were treated with EPA 30 min after fracture. Vital signs were recorded and serum concentrations of tumor necrosis factor-alpha (TNFalpha) and respiratory burst of neutrophils were assessed. Survival of controls was 7.7% and of animals treated with EPA 50% (log-rank: 5.162; p: 0.023). Vital signs of both groups did not differ. Oxidative burst of neutrophils was greater among EPA-treated animals compared with controls at 48 h (p: 0.010). Serum levels of TNFalpha of the former group were decreased compared with the latter at 48 h (p: 0.019). Bacterial growth of enterobacteriaceae from liver and spleen after death or euthanasia was lower among EPA-treated rabbits than controls. These results suggest that EPA possesses considerable immunomodulatory activities improving survival in a model of lethal trauma. Restoration of oxidative burst conferring efficient phagocytosis of evading bacteria seems the most probable mechanism of action.
Assuntos
Ácido Eicosapentaenoico/farmacologia , Fraturas do Fêmur/sangue , Fraturas do Fêmur/tratamento farmacológico , Mediadores da Inflamação/sangue , Fator de Necrose Tumoral alfa/sangue , Animais , Modelos Animais de Doenças , Enterobacteriaceae/crescimento & desenvolvimento , Fraturas do Fêmur/microbiologia , Humanos , Inflamação/sangue , Inflamação/tratamento farmacológico , Fígado/metabolismo , Fígado/microbiologia , Masculino , Neutrófilos/metabolismo , Fagocitose/efeitos dos fármacos , Coelhos , Explosão Respiratória/efeitos dos fármacos , Baço/metabolismo , Baço/microbiologiaRESUMO
BACKGROUND: The pandemic by the novel H1N1 virus has created the need to study any probable effects of that infection in the immune system of the host. METHODOLOGY/PRINCIPAL FINDINGS: Blood was sampled within the first two days of the presentation of signs of infection from 10 healthy volunteers; from 18 cases of flu-like syndrome; and from 31 cases of infection by H1N1 confirmed by reverse RT-PCR. Absolute counts of subtypes of monocytes and of lymphocytes were determined after staining with monoclonal antibodies and analysis by flow cytometry. Peripheral blood mononuclear cells (PBMCs) were isolated from patients and stimulated with various bacterial stimuli. Concentrations of tumour necrosis factor-alpha, interleukin (IL)-1beta, IL-6, IL-18, interferon (FN)-alpha and of IFN-gamma were estimated in supernatants by an enzyme immunoassay. Infection by H1N1 was accompanied by an increase of monocytes. PBMCs of patients evoked strong cytokine production after stimulation with most of bacterial stimuli. Defective cytokine responses were shown in response to stimulation with phytohemagglutin and with heat-killed Streptococcus pneumoniae. Adaptive immune responses of H1N1-infected patients were characterized by decreases of CD4-lymphocytes and of B-lymphocytes and by increase of T-regulatory lymphocytes (Tregs). CONCLUSIONS/SIGNIFICANCE: Infection by the H1N1 virus is accompanied by a characteristic impairment of the innate immune responses characterized by defective cytokine responses to S.pneumoniae. Alterations of the adaptive immune responses are predominated by increase of Tregs. These findings signify a predisposition for pneumococcal infections after infection by H1N1 influenza.