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2.
J Clin Psychol Med Settings ; 30(2): 425-434, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-35778655

RESUMO

Physicians are experiencing epidemic levels of work-related stress and burnout. Determine efficacy of mindfulness meditation delivered as a hybrid (in-person and digital) format to reduce perceived stress in pediatric residents. Pediatric residents (n = 66) were block randomized to a hybrid Mindful Awareness Practices (MAPs) intervention, comprised of one in-person 60-min session and 6-week access to a digitally delivered MAPs curriculum (n = 27) or wait-list control (n = 39). Perceived Stress Scale (PSS) was administered at baseline and post-intervention as the primary outcome measure. A priori secondary outcomes were measured using the Abbreviated Maslach Burnout Inventory-9, Beck Depression Inventory, Beck Anxiety Inventory, UCLA Loneliness Scale, and Pittsburgh Sleep Quality Index. After the first session, 58% participated at least one digital session (M = 2.0; SD = 1.3). MAPs participants showed significant decrease in PSS compared to controls, with between-group mean difference of 2.20 (95% CI 0.47-3.93) at post-intervention (effect size 0.91; 0.19-1.62). No secondary outcome group differences were detected. Exposure to a hybrid mindfulness intervention was associated with improvement in perceived stress among pediatric residents.Trial Registration: NCT03613441.


Assuntos
Esgotamento Profissional , Meditação , Atenção Plena , Médicos , Humanos , Criança , Currículo
3.
Lancet Child Adolesc Health ; 6(10): 725-737, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35931098

RESUMO

Paediatric acute liver failure (PALF) is defined as a biochemical evidence of acute liver injury in a child with no previous history of chronic liver disease characterised by an international normalised ratio (INR) of 1·5 or more unresponsive to vitamin K with encephalopathy, or INR of 2·0 or more with or without encephalopathy. PALF can rapidly progress to multiorgan dysfunction or failure. Although the transplant era has substantially changed the outlook for these patients, transplantation itself is not without risks, including those associated with life-long immunosuppression. Consequently, there has been an increased focus on improving medical management to prioritise bridging of patients to native liver survival, which is possible due to improved understanding of the underlying pathophysiology of multiorgan involvement in PALF. In this Review, we discuss recent advances in the medical management of PALF with an aim of reducing the need for liver transplantation. The Review will focus on the non-specific immune-mediated inflammatory response, extracorporeal support devices, neuromonitoring and neuroprotection, and emerging cellular and novel future therapeutic options.


Assuntos
Encefalopatias , Falência Hepática Aguda , Transplante de Fígado , Criança , Humanos , Falência Hepática Aguda/complicações , Falência Hepática Aguda/terapia , Vitamina K/uso terapêutico
5.
J Paediatr Child Health ; 58(2): 228-231, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34674333

RESUMO

There are many reasons why the international community as a whole should advocate for COVID-19 vaccine equity: global economic recession, uncontrolled outbreaks with higher risk of virus variants and persistent unsafe travelling in an era of now vaccine-preventable cause of death. This inequity is an avoidable threat to global health. Funding agencies, policy makers, drug companies and NGOs among others have the moral duty to end this vaccine apartheid and to make vaccine equity a reality. In this viewpoint, we discuss how inequalities in vaccination access affect a proper control of the pandemic, highlighting specific consequences on child health.


Assuntos
COVID-19 , Vacinas , Apartheid , Vacinas contra COVID-19 , Criança , Humanos , Pandemias/prevenção & controle , SARS-CoV-2
6.
Front Pediatr ; 9: 628810, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33643977

RESUMO

During the COVID pandemic, a surge in pediatric Type 1 Diabetes Mellitus (T1DM) cases appears to be occurring, potentially due to the presence of autoantibody-induced immune dysregulation triggered by COVID-19. We describe one such case in a previously healthy 7-year-old with asymptomatic COVID-19 presenting with a high nasopharyngeal SARS CoV-2 virus load, detectable COVID-19 IgG antibodies, diabetic keto-acidosis and islet cell autoantibodies. COVID-19 is not a trivial disease in children and adolescents and can lead to lifelong sequelae such as T1DM. Raising awareness about a possible association between COVID-19 and T1DM in children is critical.

7.
Front Pediatr ; 8: 618119, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33425821

RESUMO

Pediatric Acute Liver Failure (PALF) is a rapidly progressive clinical syndrome encountered in the pediatric ICU which may rapidly progress to multi-organ dysfunction, and on occasion to life threatening cerebral edema and hemorrhage. Pediatric Acute Liver Failure is defined as severe acute hepatic dysfunction accompanied by encephalopathy and liver-based coagulopathy defined as prolongation of International Normalized Ratio (INR) >1.5. However, coagulopathy in PALF is complex and warrants a deeper understanding of the hemostatic balance in acute liver failure. Although an INR value of >1.5 is accepted as the evidence of coagulopathy and has historically been viewed as a prognostic factor of PALF, it may not accurately reflect the bleeding risk in PALF since it only measures procoagulant factors. Paradoxically, despite the prolongation of INR, bleeding risk is lower than expected (around 5%). This is due to "rebalanced hemostasis" due to concurrent changes in procoagulant, anticoagulant and fibrinolytic systems. Since the liver is involved in both procoagulant (Factors II, V, IX, XI, and fibrinogen) and anticoagulant (Protein C, Protein S, and antithrombin) protein synthesis, PALF results in "rebalanced hemostasis" or even may shift toward a hypercoagulable state. In addition to rebalanced coagulation there is altered platelet production due to decreased thrombopoietin production by liver, increased von Willebrand factor from low grade endothelial cell activation, and hyperfibrinolysis and dysfibrinogenemia from altered synthetic liver dysfunction. All these alterations contribute to the multifactorial nature of coagulopathy in PALF. Over exuberant use of prophylactic blood products in patients with PALF may contribute to morbidities such as fluid overload, transfusion-associated lung injury, and increased thrombosis risk. It is essential to use caution when using INR values for plasma and factor administration. In this review we will summarize the complexity of coagulation in PALF, explore "rebalanced hemostasis," and discuss the limitations of current coagulation tests. We will also review strategies to accurately diagnose the coagulopathy of PALF and targeted therapies.

8.
Hosp Pediatr ; 10(1): 61-69, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31879317

RESUMO

BACKGROUND AND OBJECTIVES: Chart reviews are frequently used for research, care assessments, and quality improvement activities despite an absence of data on reliability and validity. We aim to describe a structured chart review methodology and to establish its validity and reliability. METHODS: A generalizable structured chart review methodology was designed to evaluate causes of morbidity or mortality and to identify potential therapeutic advances. The review process consisted of a 2-tiered approach with a primary review completed by a site physician and a short secondary review completed by a central physician. A total of 327 randomly selected cases of known mortality or new morbidities were reviewed. Validity was assessed by using postreview surveys with a Likert scale. Reliability was assessed by percent agreement and interrater reliability. RESULTS: The primary reviewers agreed or strongly agreed in 94.9% of reviews that the information to form a conclusion about pathophysiological processes and therapeutic advances could be adequately found. They agreed or strongly agreed in 93.2% of the reviews that conclusions were easy to make, and confidence in the process was 94.2%. Secondary reviewers made modifications to 36.6% of cases. Duplicate reviews (n = 41) revealed excellent percent agreement for the causes (80.5%-100%) and therapeutic advances (68.3%-100%). κ statistics were strong for the pathophysiological categories but weaker for the therapeutic categories. CONCLUSIONS: A structured chart review by knowledgeable primary reviewers, followed by a brief secondary review, can be valid and reliable.


Assuntos
Auditoria Médica , Prontuários Médicos , Humanos , Morbidade , Mortalidade , Reprodutibilidade dos Testes , Inquéritos e Questionários
9.
J Pediatr Intensive Care ; 8(2): 103-107, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31093464

RESUMO

Infective endocarditis (IE) in the pediatric population is uncommon and presents with nonspecific signs. Nonetheless, prompt diagnosis and management are critical given its high mortality rate. We present the case of a 15-year-old boy who initially presented with bilateral multifocal pneumonia and was found to have IE with a right ventricular vegetation. The vegetation was removed percutaneously, obviating a more invasive surgical approach. The patient tolerated the procedure well and rapidly improved following removal of the vegetation. This case report highlights the utility of a novel, minimally invasive approach for the management of cardiac masses.

10.
J Pediatr Nurs ; 43: 62-68, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30473158

RESUMO

PURPOSE: The primary goal of this study was to test the feasibility of an educational online self-assessment of burnout, resilience, trauma, depression, anxiety, and common workplace stressors among nurses working in a pediatric intensive care unit or neonatal intensive care unit setting. The secondary, exploratory objectives were to estimate the prevalence of psychiatric symptoms in this sample and to identify those variables that most strongly predict burnout. DESIGN AND METHODS: Data from optional and anonymous online measures were analyzed for 115 nurses (67.9% aged 25-44; 61.7% Caucasian) working in an urban children's hospital pediatric or neonatal ICU. Multiple linear regressions identified demographic variables and workplace stressors that significantly predicted each of three components of burnout. RESULTS: Most respondents found the educational assessment and feedback to be helpful. Choosing nursing as a second career was associated with better resilience. Having worked in ICU settings longer and being older were both linked to lower levels of anxiety. Predictors of burnout varied across the three burnout subscales. CONCLUSIONS: Implementation of an online self-assessment with immediate educational feedback is feasible in critical care settings. The variability of predictors across the three burnout subscales indicates the need for tailored interventions for those at risk. Future research may include follow-up of nurses to examine changes in scores over time and expansion of the tool for other medical personnel. PRACTICE IMPLICATIONS: An educational online self-assessment can be a helpful tool for pediatric critical care nurses experiencing varying degrees of burnout and distress.


Assuntos
Esgotamento Profissional/psicologia , Cuidados Críticos/métodos , Saúde Mental , Comportamento de Redução do Risco , Autoavaliação (Psicologia) , Adulto , Pré-Escolar , Educação a Distância , Estudos de Viabilidade , Retroalimentação , Feminino , Hospitais Pediátricos , Humanos , Lactente , Unidades de Terapia Intensiva Neonatal , Unidades de Terapia Intensiva Pediátrica , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Enfermagem Neonatal/métodos , Enfermagem Pediátrica/métodos , Projetos Piloto , Qualidade de Vida , Estados Unidos , Adulto Jovem
11.
Infect Immun ; 86(7)2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29735522

RESUMO

Iron is an essential micronutrient for most microbes and their hosts. Mammalian hosts respond to infection by inducing the iron-regulatory hormone hepcidin, which causes iron sequestration and a rapid decrease in the plasma and extracellular iron concentration (hypoferremia). Previous studies showed that hepcidin regulation of iron is essential for protection from infection-associated mortality with the siderophilic pathogens Yersinia enterocolitica and Vibrio vulnificus However, the evolutionary conservation of the hypoferremic response to infection suggests that not only rare siderophilic bacteria but also common pathogens may be targeted by this mechanism. We tested 10 clinical isolates of Escherichia coli from children with sepsis and found that both genetic iron overload (by hepcidin-1 knockout [HKO]) and iatrogenic iron overload (by intravenous iron) potentiated infection with 8 out of the 10 studied isolates: after peritoneal injection of E. coli, iron-loaded mice developed sepsis with 60% to 100% mortality within 24 h, while control wild-type mice suffered 0% mortality. Using one strain for more detailed study, we show that iron overload allows rapid bacterial multiplication and dissemination. We further found that the presence of non-transferrin-bound iron (NTBI) in the circulation is more important than total plasma or tissue iron in rendering mice susceptible to infection and mortality. Postinfection treatment of HKO mice with just two doses of the hepcidin agonist PR73 abolished NTBI and completely prevented sepsis-associated mortality. We demonstrate that the siderophilic phenotype extends to clinically common pathogens. The use of hepcidin agonists promises to be an effective early intervention in patients with infections and dysregulated iron metabolism.


Assuntos
Bacteriemia/mortalidade , Infecções por Escherichia coli/mortalidade , Hepcidinas/fisiologia , Animais , Bacteriemia/etiologia , Bacteriemia/microbiologia , Criança , Infecções por Escherichia coli/etiologia , Infecções por Escherichia coli/microbiologia , Hepcidinas/agonistas , Humanos , Ferro/metabolismo , Sobrecarga de Ferro/complicações , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transferrina/análise
12.
Pediatr Clin North Am ; 64(5): 1017-1037, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28941533

RESUMO

Acute respiratory distress syndrome (ARDS) is a syndrome of noncardiogenic pulmonary edema and hypoxia that accompanies up to 30% of deaths in pediatric intensive care units. Pediatric ARDS (PARDS) is diagnosed by the presence of hypoxia, defined by oxygenation index or Pao2/Fio2 ratio cutoffs, and new chest infiltrate occurring within 7 days of a known insult. Hallmarks of ARDS include hypoxemia and decreased lung compliance, increased work of breathing, and impaired gas exchange. Mortality is often accompanied by multiple organ failure. Although many modalities to treat PARDS have been investigated, supportive therapies and lung protective ventilator support remain the mainstay.


Assuntos
Cuidados Críticos/métodos , Insuficiência Respiratória/fisiopatologia , Insuficiência Respiratória/terapia , Doença Aguda , Criança , Terapia Combinada , Dietoterapia , Circulação Extracorpórea , Hidratação/métodos , Humanos , Respiração Artificial/efeitos adversos , Respiração Artificial/métodos , Síndrome
13.
Blood ; 130(3): 245-257, 2017 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-28465342

RESUMO

The iron-regulatory hormone hepcidin is induced early in infection, causing iron sequestration in macrophages and decreased plasma iron; this is proposed to limit the replication of extracellular microbes, but could also promote infection with macrophage-tropic pathogens. The mechanisms by which hepcidin and hypoferremia modulate host defense, and the spectrum of microbes affected, are poorly understood. Using mouse models, we show that hepcidin was selectively protective against siderophilic extracellular pathogens (Yersinia enterocolitica O9) by controlling non-transferrin-bound iron (NTBI) rather than iron-transferrin concentration. NTBI promoted the rapid growth of siderophilic but not nonsiderophilic bacteria in mice with either genetic or iatrogenic iron overload and in human plasma. Hepcidin or iron loading did not affect other key components of innate immunity, did not indiscriminately promote intracellular infections (Mycobacterium tuberculosis), and had no effect on extracellular nonsiderophilic Y enterocolitica O8 or Staphylococcus aureus Hepcidin analogs may be useful for treatment of siderophilic infections.


Assuntos
Infecções Relacionadas a Cateter/imunologia , Hemocromatose/imunologia , Hepcidinas/imunologia , Sobrecarga de Ferro/imunologia , Ferro/metabolismo , Infecções Estafilocócicas/imunologia , Animais , Ligação Competitiva , Infecções Relacionadas a Cateter/metabolismo , Infecções Relacionadas a Cateter/microbiologia , Infecções Relacionadas a Cateter/mortalidade , Modelos Animais de Doenças , Resistência à Doença , Expressão Gênica , Hemocromatose/metabolismo , Hemocromatose/microbiologia , Hemocromatose/mortalidade , Hepcidinas/agonistas , Hepcidinas/deficiência , Hepcidinas/genética , Humanos , Ferro/imunologia , Sobrecarga de Ferro/metabolismo , Sobrecarga de Ferro/microbiologia , Sobrecarga de Ferro/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/crescimento & desenvolvimento , Mycobacterium tuberculosis/metabolismo , Oligopeptídeos/farmacologia , Ligação Proteica , Infecções Estafilocócicas/metabolismo , Infecções Estafilocócicas/microbiologia , Infecções Estafilocócicas/mortalidade , Staphylococcus aureus , Análise de Sobrevida , Transferrina/genética , Transferrina/metabolismo , Yersinia enterocolitica/efeitos dos fármacos , Yersinia enterocolitica/crescimento & desenvolvimento , Yersinia enterocolitica/metabolismo
14.
Clin Respir J ; 10(1): 48-53, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24989058

RESUMO

BACKGROUND AND AIMS: COPD (chronic obstructive pulmonary disease) is a very heterogeneous disease, and phenotypic categorization of a high-risk population has many potential benefits. The present study uses a symptom questionnaire, low-dose computed tomography (LDCT) and pulmonary function tests (PFT) to phenotypically subgroup a high-risk population. METHODS: Study group consisted of current or former smokers who underwent lung cancer screening with LDCT as a subgroup of Pittsburgh Lung Screening Study. In addition to LDCT, PFT and a symptom query questionnaire were obtained from each patient. RESULTS: The study group consisted of 3183 subjects (age 50-79) subdivided into eight groups according to presence of symptoms, obstruction on PFT and presence of emphysema on LDCT. A total of 501 (15.7%) subjects were asymptomatic, with no airflow obstruction or evidence of emphysema. There were 866 (27.2%) subjects with both obstruction on PFT and emphysema on LDCT, but only 660 (20.7%) had symptoms. Five hundred thirty (16.6%) of the subjects had no emphysema on LDCT but had obstruction on PFT, although only 370 (11.6%) had symptoms. Four hundred seventy-four (14.9%) of subjects had emphysema on LDCT, but no airflow obstruction, with 312 (9.8%) symptomatic. Finally, 812 (25.5%) of subjects had no evidence of airflow obstruction on PFT or emphysema on LDCT, but had symptoms. CONCLUSION: Combining LDCT with PFT and a comprehensive questionnaire allows subgroup classification of COPD phenotypes in a high-risk population and may lead to earlier intervention and an improved framework for future studies.


Assuntos
Neoplasias Pulmonares/diagnóstico , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Idoso , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Pennsylvania/epidemiologia , Fenótipo , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Enfisema Pulmonar/diagnóstico , Enfisema Pulmonar/diagnóstico por imagem , Testes de Função Respiratória/métodos , Fumar/epidemiologia , Inquéritos e Questionários , Tomografia Computadorizada por Raios X/métodos
15.
Cell Host Microbe ; 17(1): 47-57, 2015 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-25590758

RESUMO

Hereditary hemochromatosis, an iron overload disease caused by a deficiency in the iron-regulatory hormone hepcidin, is associated with lethal infections by siderophilic bacteria. To elucidate the mechanisms of this susceptibility, we infected wild-type and hepcidin-deficient mice with the siderophilic bacterium Vibrio vulnificus and found that hepcidin deficiency results in increased bacteremia and decreased survival of infected mice, which can be partially ameliorated by dietary iron depletion. Additionally, timely administration of hepcidin agonists to hepcidin-deficient mice induces hypoferremia that decreases bacterial loads and rescues these mice from death, regardless of initial iron levels. Studies of Vibrio vulnificus growth ex vivo show that high iron sera from hepcidin-deficient mice support extraordinarily rapid bacterial growth and that this is inhibited in hypoferremic sera. Our findings demonstrate that hepcidin-mediated hypoferremia is a host defense mechanism against siderophilic pathogens and suggest that hepcidin agonists may improve infection outcomes in patients with hereditary hemochromatosis or thalassemia.


Assuntos
Bacteriemia/imunologia , Hepcidinas/metabolismo , Ferro/metabolismo , Vibrioses/imunologia , Vibrio vulnificus/crescimento & desenvolvimento , Vibrio vulnificus/imunologia , Animais , Bacteriemia/microbiologia , Carga Bacteriana , Mecanismos de Defesa , Hepcidinas/deficiência , Ferro/sangue , Camundongos Endogâmicos C57BL , Camundongos Knockout , Vibrioses/microbiologia
16.
Infect Immun ; 82(2): 745-52, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24478088

RESUMO

Hepcidin, the iron-regulatory hormone, is increased during infection or inflammation, causing hypoferremia. This response is thought to be a host defense mechanism that restricts iron availability to invading pathogens. It is not known if hepcidin is differentially induced by bacterial versus viral infections, whether the stimulation of pattern recognition receptors directly regulates hepcidin transcription, or which of the proposed signaling pathways are essential for hepcidin increase during infection. We analyzed hepcidin induction and its dependence on interleukin-6 (IL-6) in response to common bacterial or viral infections in mice or in response to a panel of pathogen-derived molecules (PAMPs) in mice and human primary hepatocytes. In wild-type (WT) mice, hepcidin mRNA was induced several hundred-fold both by a bacterial (Streptococcus pneumoniae) and a viral infection (influenza virus PR8) within 2 to 5 days. Treatment of mice and human primary hepatocytes with most Toll-like receptor ligands increased hepcidin mRNA within 6 h. Hepcidin induction by microbial stimuli was IL-6 dependent. IL-6 knockout mice failed to increase hepcidin in response to S. pneumoniae or influenza infection and had greatly diminished hepcidin response to PAMPs. In vitro, hepcidin induction by PAMPs in primary human hepatocytes was abolished by the addition of neutralizing IL-6 antibodies. Our results support the key role of IL-6 in hepcidin regulation in response to a variety of infectious and inflammatory stimuli.


Assuntos
Hepatócitos/microbiologia , Hepatócitos/virologia , Hepcidinas/biossíntese , Interleucina-6/metabolismo , Animais , Hepatócitos/imunologia , Hepatócitos/metabolismo , Humanos , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Orthomyxoviridae/imunologia , Streptococcus pneumoniae/imunologia
17.
J Immunol ; 184(11): 6359-66, 2010 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-20435923

RESUMO

Myeloid differentiation factor 2 (MD-2) is a secreted gp that assembles with TLR4 to form a functional signaling receptor for bacterial LPS. In this study, we have identified a novel alternatively spliced isoform of human MD-2, termed MD-2 short (MD-2s), which lacks the region encoded by exon 2 of the MD-2 gene. Similar to MD-2, MD-2s is glycosylated and secreted. MD-2s also interacted with LPS and TLR4, but failed to mediate LPS-induced NF-kappaB activation and IL-8 production. We show that MD-2s is upregulated upon IFN-gamma, IL-6, and TLR4 stimulation and negatively regulates LPS-mediated TLR4 signaling. Furthermore, MD-2s competitively inhibited binding of MD-2 to TLR4. Our study pinpoints a mechanism that may be used to regulate TLR4 activation at the onset of signaling and identifies MD-2s as a potential therapeutic candidate to treat human diseases characterized by an overly exuberant or chronic immune response to LPS.


Assuntos
Lipopolissacarídeos/imunologia , Antígeno 96 de Linfócito/genética , Transdução de Sinais/imunologia , Receptor 4 Toll-Like/genética , Linhagem Celular , Separação Celular , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/imunologia , Humanos , Immunoblotting , Imunoprecipitação , Interleucina-8/biossíntese , Antígeno 96 de Linfócito/imunologia , Antígeno 96 de Linfócito/metabolismo , Microscopia Confocal , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Isoformas de Proteínas/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptor 4 Toll-Like/imunologia , Receptor 4 Toll-Like/metabolismo
18.
Infect Immun ; 77(7): 2683-90, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19398543

RESUMO

Heat shock protein 60 derived from Chlamydia pneumoniae (cHSP60) activates Toll-like receptor 4 (TLR4) signaling through the MyD88 pathway in vitro, but it is not known how cHSP60 contributes to C. pneumoniae-induced lung inflammation. We treated wild-type (WT), TLR2(-/-), TLR4(-/-), or MyD88(-/-) mice intratracheally (i.t.) with recombinant cHSP60 (50 microg), UV-killed C. pneumoniae (UVCP; 5 x 10(6) inclusion-forming units/mouse), lipopolysaccharide (2 microg), or phosphate-buffered saline (PBS) and sacrificed mice 24 h later. Bronchoalveolar lavage (BAL) was obtained to measure cell counts and cytokine levels, lungs were analyzed for histopathology, and lung homogenate chemokine concentrations were determined. Bone marrow-derived dendritic cells (BMDDCs) were generated and stimulated with live C. pneumoniae (multiplicity of infection [MOI], 5), UVCP (MOI, 5), or cHSP60 for 24 h, and the expression of costimulatory molecules (CD80 and CD86) was measured by fluorescence-activated cell sorting. cHSP60 induced acute lung inflammation with the same intensity as that of UVCP-induced inflammation in WT mice but not in TLR4(-/-) or MyD88(-/-) mice. cHSP60- and UVCP-induced lung inflammation was associated with increased numbers of cells in BAL, increased neutrophil recruitment, and elevated BAL interleukin-6 (IL-6) levels. Both cHSP60 and UVCP induced IL-6 release and CD80 and CD86 expression in WT cells but not in MyD88(-/-) BMDDCs. cHSP60 stimulated DC activation in a TLR4- and MyD88-dependent manner with an intensity similar to that induced by UVCP. These data suggest that cHSP60 promotes lung inflammation and DC activation via TLR4 and MyD88 and therefore may play a significant role in the pathogenesis of C. pneumoniae-induced chronic inflammatory lung diseases.


Assuntos
Chaperonina 60/fisiologia , Chlamydophila pneumoniae/patogenicidade , Fator 88 de Diferenciação Mieloide/imunologia , Pneumonia Bacteriana/imunologia , Pneumonia Bacteriana/patologia , Receptor 4 Toll-Like/imunologia , Animais , Antígeno B7-1/biossíntese , Antígeno B7-2/biossíntese , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/análise , Células Dendríticas/imunologia , Pulmão/química , Pulmão/imunologia , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/deficiência , Pneumonia Bacteriana/microbiologia , Receptor 4 Toll-Like/deficiência
19.
J Immunol ; 181(10): 7176-85, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18981139

RESUMO

Experimental and clinical studies link Chlamydia pneumoniae infection to atherogenesis and atherothrombotic events, but the underlying mechanisms are unclear. We tested the hypothesis that C. pneumoniae-induced acceleration of atherosclerosis in apolipoprotein E (ApoE)(-/-) mice is reciprocally modulated by activation of TLR-mediated innate immune and liver X receptor alpha (LXRalpha) signaling pathways. We infected ApoE(-/-) mice and ApoE(-/-) mice that also lacked TLR2, TLR4, MyD88, or LXRalpha intranasally with C. pneumoniae followed by feeding of a high fat diet for 4 mo. Mock-infected littermates served as controls. Atherosclerosis was assessed in aortic sinuses and in en face preparation of whole aorta. The numbers of activated dendritic cells (DCs) within plaques and the serum levels of cholesterol and proinflammatory cytokines were also measured. C. pneumoniae infection markedly accelerated atherosclerosis in ApoE-deficient mice that was associated with increased numbers of activated DCs in aortic sinus plaques and higher circulating levels of MCP-1, IL-12p40, IL-6, and TNF-alpha. In contrast, C. pneumoniae infection had only a minimal effect on atherosclerosis, accumulation of activated DCs in the sinus plaques, or circulating cytokine increases in ApoE(-/-) mice that were also deficient in TLR2, TLR4, or MyD88. However, C. pneumoniae-induced acceleration of atherosclerosis in ApoE(-/-) mice was further enhanced in ApoE(-/-)LXRalpha(-/-) double knockout mice and was accompanied by higher serum levels of IL-6 and TNF-alpha. We conclude that C. pneumoniae infection accelerates atherosclerosis in hypercholesterolemic mice predominantly through a TLR/MyD88-dependent mechanism and that LXRalpha appears to reciprocally modulate and reduce the proatherogenic effects of C. pneumoniae infection.


Assuntos
Aterosclerose/microbiologia , Infecções por Chlamydia/complicações , Proteínas de Ligação a DNA/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/fisiologia , Receptores Toll-Like/metabolismo , Animais , Aorta/imunologia , Aorta/patologia , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Infecções por Chlamydia/metabolismo , Chlamydophila pneumoniae , Citocinas/sangue , Citocinas/imunologia , Proteínas de Ligação a DNA/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Imunofluorescência , Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/biossíntese , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Hipercolesterolemia/complicações , Imuno-Histoquímica , Receptores X do Fígado , Camundongos , Camundongos Knockout , Fator 88 de Diferenciação Mieloide/genética , Análise de Sequência com Séries de Oligonucleotídeos , Receptores Nucleares Órfãos , Receptores Citoplasmáticos e Nucleares/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Receptores Toll-Like/genética
20.
J Immunol ; 181(10): 7186-93, 2008 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-18981140

RESUMO

Chlamydia pneumoniae is detected by macrophages and other APCs via TLRs and can exacerbate developing atherosclerotic lesions, but how that occurs is not known. Liver X receptors (LXRs) centrally control reverse cholesterol transport, but also negatively modulate TLR-mediated inflammatory pathways. We isolated peritoneal macrophages from wild-type, TLR2, TLR3, TLR4, TLR2/4, MyD88, TRIF, MyD88/TRIF, and IFN regulatory factor 3 (IRF3) KO mice, treated them with live or UV-killed C. pneumoniae in the presence or absence of oxidized LDL, then measured foam cell formation. In some experiments, the synthetic LXR agonist GW3965 was added to macrophages infected with C. pneumoniae in the presence of oxidized LDL. Both live and UV-killed C. pneumoniae induced IRF3 activation and promoted foam cell formation in wild-type macrophages, whereas the genetic absence of TLR2, TLR4, MyD88, TRIF, or IRF3, but not TLR3, significantly reduced foam cell formation. C. pneumoniae-induced foam cell formation was significantly reduced by the LXR agonist GW3965, which in turn inhibited C. pneumoniae-induced IRF3 activation, suggesting a bidirectional cross-talk. We conclude that C. pneumoniae facilitates foam cell formation via activation of both MyD88-dependent and MyD88-independent (i.e., TRIF-dependent and IRF3-dependent) pathways downstream of TLR2 and TLR4 signaling and that TLR3 is not involved in this process. This mechanism could at least partly explain why infection with C. pneumoniae accelerates the development of atherosclerotic plaque and lends support to the proposal that LXR agonists might prove clinically useful in suppressing atherogenesis.


Assuntos
Infecções por Chlamydia/metabolismo , Proteínas de Ligação a DNA/metabolismo , Células Espumosas/microbiologia , Fator 88 de Diferenciação Mieloide/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Transdução de Sinais/fisiologia , Animais , Aterosclerose/metabolismo , Aterosclerose/microbiologia , Benzoatos/farmacologia , Benzilaminas/farmacologia , Infecções por Chlamydia/complicações , Chlamydophila pneumoniae , Células Espumosas/metabolismo , Fator Regulador 3 de Interferon/metabolismo , Lipoproteínas LDL/metabolismo , Receptores X do Fígado , Camundongos , Camundongos Knockout , NF-kappa B/metabolismo , Receptores Nucleares Órfãos , Receptores Toll-Like/metabolismo
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