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STRUCTURAL AND TOPOGRAPHIC DYNAMICS OF PULMONARY HISTOPATHOLOGY AND LOCAL CYTOKINE PROFILES IN PARACOCCIDIOIDES BRASILIENSIS CONIDIA-INFECTED MICE
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Corporación para Investigaciones Biológicas. Medical and Experimental Mycology Group. Medellín, Colômbia.
Corporación para Investigaciones Biológicas. Medical and Experimental Mycology Group, Medellín, Colômbia / Universidad Pontificia Bolivarina. School of Health Sciences. Medellín, Colômbia.
Fundação Oswaldo Cruz. Presidência. Programa de Computação Científica.Rio de Janeiro, Brasil.
Corporación para Investigaciones Biológicas. Medical and Experimental Mycology Group. Medellín, Colômbia.
Corporación para Investigaciones Biológicas. Medical and Experimental Mycology Group. Medellín, Colômbia / Universidad Pontificia Bolivarina. School of Health Sciences. Medellín, Colômbia / Universidad de Antioquia. Microbiology School. Medellín, Colômbia.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Patologia. Rio de Janeiro, RJ, Brasil.
Corporación para Investigaciones Biológicas. Medical and Experimental Mycology Group, Medellín, Colômbia / Universidad Pontificia Bolivarina. School of Health Sciences. Medellín, Colômbia.
Fundação Oswaldo Cruz. Presidência. Programa de Computação Científica.Rio de Janeiro, Brasil.
Corporación para Investigaciones Biológicas. Medical and Experimental Mycology Group. Medellín, Colômbia.
Corporación para Investigaciones Biológicas. Medical and Experimental Mycology Group. Medellín, Colômbia / Universidad Pontificia Bolivarina. School of Health Sciences. Medellín, Colômbia / Universidad de Antioquia. Microbiology School. Medellín, Colômbia.
Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Patologia. Rio de Janeiro, RJ, Brasil.
Abstract
Background: Paracoccidioidomycosis (PCM), an endemic systemic mycosis caused by the fungus Paracoccidioides brasiliensis (Pb), usually results in severe lung damage in patients. Methods and Findings: Considering the difficulties to sequentially study the infection in humans, this work was done in mice inoculated intranasally with infective Pb-conidia. Lungs of control and Pb-infected mice were studied after 2-hours, 4, 8, 12 and 16-weeks post-infection (p.i) in order to define histopathologic patterns of pulmonary lesions, multiplex-cytokine profiles and their dynamics during the course of this mycosis. Besides the nodular/granulomatous lesions previously informed, results revealed additional non-formerly described lung abnormalities, such as periarterial sheath inflammation and pseudotumoral masses. The following chronologic stages occurring during the course of the experimental infection were defined: Stage one (2-hours p.i): mild septal infiltration composed by neutrophils and macrophages accompanied by
an intense ‘‘cytokine burst’’ represented by significant increases in IL-1a, IL-1b, IL-4, IL-5, IL-6, IL-10, IL12p70, IL-13, IL-17, Eotaxin, G-CSF, MCP1, MIP1a, GM-CSF, IFN-c, MIP1b and TNFa levels. Stage two (4-weeks p.i): presence of nodules, evidence of incipient periarterial- and intense but disperse parenchymal- inflammation, abnormalities that continued to be
accompanied by hyper-secretion of those cytokines and chemokines mentioned in the first stage of infection. Stages three and four (8 and 12-weeks p.i.): fungal proliferation, inflammation and collagenesis reached their highest intensity with particular involvement of the periarterial space. Paradoxically, lung cytokines and chemokines were down-regulated with
significant decreases in IL-2,IL-3,IL-5,IL-9,IL-13,IL-15,GM-CSF,IFN-c,MIP1b and TNFa. Stage five (16-weeks p.i.): inflammation decreased becoming limited to the pseudotumoral masses and was accompanied by a ‘‘silent’’ cytokine response, except for PDGF, MIG, RANTES and IL12p40 which remained up-regulated for the duration of the experiment. Conclusions: Results of this study identified both classic and novel patterns corresponding to histopathologic and immunologic responses occurring during the course of experimental PCM.
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