title: Structural and topographic dynamics of pulmonary histopathology and local cytokine profiles in Paracoccidioides brasiliensis conidia-infected mice.
abstract: BACKGROUND
  Paracoccidioidomycosis (PCM), an endemic systemic mycosis caused by the fungus Paracoccidioides brasiliensis (Pb), usually results in severe lung damage in patients.
  
  
  RESULTS
  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-1α, IL-1β, IL-4, IL-5, IL-6, IL-10, IL12p70, IL-13, IL-17, Eotaxin, G-CSF, MCP1, MIP1α, GM-CSF, IFN-γ, MIP1β and TNFα 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-γ,MIP1β and TNFα. 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.
authors.affiliation: Medical and Experimental Mycology Group, Corporación para Investigaciones Biológicas, Medellín, Colombia.
authors.forename: Damaris
authors.initials: D
authors.lastname: Lopera
authors.forename: Tonny W
authors.initials: TW
authors.lastname: Naranjo
authors.forename: Oswaldo G
authors.initials: OG
authors.lastname: Cruz
authors.forename: Angela
authors.initials: A
authors.lastname: Restrepo
authors.forename: Luz Elena
authors.initials: LE
authors.lastname: Cano
authors.forename: Henrique Leonel
authors.initials: HL
authors.lastname: Lenzi
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D004195:Disease Models, Animal; D006651:Histocytochemistry; D007118:Immunoassay; D007150:Immunohistochemistry; D008168:Lung / Q000382:microbiology / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008853:Microscopy; D010228:Paracoccidioides / Q000276:immunology* / Q000472:pathogenicity*; D010229:Paracoccidioidomycosis / Q000276:immunology* / Q000473:pathology*; D012376:Rodent Diseases / Q000276:immunology / Q000473:pathology; D013172:Spores, Fungal / Q000276:immunology / Q000472:pathogenicity; D013997:Time Factors
chemical_list: D016207:Cytokines