Pulmonary immune responses to Aspergillus fumigatus in rats.

OBJECTIVE: To evaluate immunologic mechanisms underlying Aspergillus fumigatus pulmonary infections in immunocompetent Dark Agouti (DA) and Albino Oxford (AO) rats recognized as being susceptible to some inflammatory diseases in different manners. METHODS: Lung fungal burden (quantitative colony forming units, CFU, assay), leukocyte infiltration (histology, cell composition) and their function (phagocytosis, oxidative activity, CD11b adhesion molecule expression) and cytokine interferon-γ (IFN-γ) and interleukin-17 and -4 (IL-17 and IL-4) lung content were evaluated following infection (intratracheally, 1x10(7) conidia). RESULTS: Slower reduction of fungal burden was observed in AO rats in comparison with that in DA rats, which was coincided with less intense histologically evident lung cell infiltration and leukocyte recovery as well as lower level of most of the their activities including intracellular myeloperoxidase activity, the capacity of nitroblue tetrazolium salt reduction and CD11b adhesion molecule expression (except for phagocytosis of conidia) in these rats. Differential patterns of changes in proinflammatory cytokine levels (unchanged levels of IFN-γ and transient increase of IL-17 in AO rats vs continuous increase of both cytokines in DA rats) and unchanged levels of IL-4 were observed. CONCLUSION: Genetically-based differences in the pattern of antifungal lung leukocyte activities and cytokine milieu, associated with differential efficiency of fungal elimination might be useful in the future use of rat models in studies of pulmonary aspergillosis.

Regional cytokine responses to pulmonary aspergillosis in immunocompetent rats.

Rat models of pulmonary aspergillosis are used widely in diagnostic studies and in exploring antifungal therapeutic modalities, but there is lack of data concerning antifungal immunity in rats. In this study, cytokine response to pulmonary infection to Aspergillus fumigatus in non-immunosuppressed rats is explored. Temporal display (from the start of infection up to its eradication) of proinflammatory cytokines (IFN-γ and IL-17) as well as Th2/anti-inflammatory ones (IL-4 and IL-10) was explored by measuring their presence in the environment in which elimination of infection occur (lung homogenates), by production of these mediators by lung cells (recovered by enzyme digestion or by bronchoalveolar lavage) as well as by cells of draining lymph nodes (as sites of generation of cytokine-producing cells). Reduction of infection (1 × 107conidia) was associated with an increase of IFN-γ and IL-17 content in lung homogenates, but with unchanged IL-4 and IL-10 content. Lung cells produced proinflammatory cytokines with differential dynamics (IFN-γ earlier than IL-17). Differential pattern of Th2/anti-inflammatory cytokine production by lung cells was observed (unchanged IL-4 and increased IL-10), with the levels of the latter higher than proinflammatory cytokines. Upregulation of IFN-γ, IL-17 and IL-10 production and gene expression, but downregulation of IL-4, by draining lymph node cells (dLN cells) accounted essentially for the observed ex vivo cytokine response in lungs. Similar pattern of cytokine production by dLN cells following restimulation with A. fumigatus conidia confirmed the specificity of cytokine response to the fungus. Draining lymph node CD4⁺ cells seems to be the main source of proinflammatory cytokines, significant contributors to IL-10 production and the target for down regulation of IL-4. The knowledge of immune-based mechanisms of defense against A. fumigatus in rats might be helpful in the future use of rat models of pulmonary aspergillosis particularly those that develop immune-based therapeutic interventions as an adjunct treatment of fungal diseases.