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Doctoral Thesis
DOI
10.11606/T.42.2009.tde-01122009-101538
Document
Author
Full name
Simone Bernardino
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2009
Supervisor
Committee
Calich, Vera Lucia Garcia (President)
Benard, Gil
Blotta, Maria Heloisa Souza Lima
Câmara, Niels Olsen Saraiva
Gazzinelli, Ricardo Tostes
Title in Portuguese
Caracterização dos mecanismos imunológicos associados com os efeitos protetores e deletérios do óxido nitrico na Paracoccidioidomicose pulmonar.
Keywords in Portuguese
Citocinas
Granuloma
Imunologia
Linfócitos
Macrófagos
Óxido nítrico
Paracoccidioidomicose
Abstract in Portuguese
Paracoccidioidomicose é adquirida pela via respiratória e o óxido nitrico (NO) está envolvido na eliminação de patógenos. Nós propusemos investigar o papel do NO na doença em animais NO-/- sintase deficientes (iNOS-/-) e seu grupo WT. Na 2ª semana de infecção, a ausência de NO resultou em doença menos grave com aumento dos níveis de TNF-a acompanhado com o intenso afluxo de linfócitos T e macrófagos para os pulmões. Na 10ª semana, os animais iNOS-/- desenvolveram alta carga fúngica nos pulmões com menor afluxo de celulas T ativadas e macrófagos e presença de células T reguladoras CD4+CD25+FoxP3+ nos pulmões. Somente os animais iNOS-/- desenvolveram lesões pulmonares organizadas em granulomas, embora não foi detectado diferença na mortalidade para ambos os grupos. As diferenças morfológicas nas lesões foram abolidas pela depleção de TNF-a que induziu nos animais iNOS-/- uma mortalidade precoce e intenso afluxo inflamatório nos pulmões. Além disso, a depleção de linfócitos TCD8+ resultou em doença mais grave e menor recrutamento celular pulmonar nos animais iNOS-/-.
Title in English
Characterization of the immunological mechanisms associated with the protective and deleterious effects of nitric oxide in pulmonary paracoccidioidomycosis.
Keywords in English
Cytokines
Granuloma
Immunology
Lymphocytes
Macrophages
Nitric oxide
Paracoccidioidomycosis
Abstract in English
Paracoccidioidomycosis is acquired by the respiratory route and nitric oxide (NO) is involved in the killing of pathogens, we aimed to investigate the role of NO in the course of the disease using NO- synthase deficient (iNOS-/-) and WT mice. At week 2 postinfection, NO absence resulted in less severe infection associated with increased TNF-a levels besides a massive influx of activated T cells and macrophages to the lungs. By week 10, iNOS-/- mice developed increased fungal burdens allied with less pronounced influx of activated T cells and macrophages and increased presence of regulatory CD4+CD25+FoxP3+ T cells to the lungs. Only iNOS-/- mice developed organized pulmonary granulomas, although no differences in the mortality rates were detected. The differences in the morphology of lesions were partially abrogated by TNF-a depletion which, induced a precocious mortality of iNOS-/- and massive influx of inflammatory pulmonary cells. Indeed, the CD8+T cells depletion developed a more severe infection with less recruitment of pulmonary cells in iNOS-/- mice.
 
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Publishing Date
2010-03-02
 
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