The first and second scenarios, however, appear rather unlikely, because hardly any macrophages

or monocytes were observed in histopathologic analyses at day one after infection. The third scenario appears quite likely, because histopathological analysis revealed a strong infiltration of neutrophils encasing ungerminated conidia. In contrast, functionally attenuated neutrophils and macrophages in corticosteroid-treated mice allowed development of invasive disease despite robust cellular recruitment in the lung parenchyma.   The treatment of mice with cortisone acetate or the combination of clodrolip and cortisone acetate led to 100% mortality and invasive fungal growth within the lung tissue. Although systemic administration of corticosteroids increases the number of circulating neutrophils by three- to fivefold [31], their ability to damage A. fumigatus hyphae is strongly reduced [32]. One day post-infection,

the lung tissue showed learn more LY294002 nmr an extensive neutrophilic infiltration that surrounded germinating conidia. These neutrophils were able to delay uncontrolled tissue invasion by killing some proportion of fungal hyphae. As a consequence of the neutrophil infiltration severe tissue damage accompanied by parenchymal destruction (necrosis) was observed, leading to a decreased bioluminescence as described above. It is also noteworthy that under cortisone acetate treatment the efficiency of alveolar macrophages in inhibiting conidial germination after phagocytosis was strongly defective. None of the other treatment groups yielded hyphal germlings as early as one day post-infection. It could be assumed that this rapid germination is due to growth stimulation

via A. fumigatus corticosteroid receptors [33]. However, experiments, in which different concentrations of cortisone acetate were added to A. fumigatus cultures, neither stimulated conidia germination, nor increased the light https://www.selleckchem.com/products/pi3k-hdac-inhibitor-i.html emission (data not shown). Since new cortisone acetate itself constitutes an “”inactive”" corticosteroid derivative, which is converted into “”active”" cortisol during metabolism in the liver [34], it might be possible that a stimulation of germination is only mediated by this metabolite rather than by cortisone acetate. Another possibility for the rapid germination of conidia is given by a neutrophil mediated tissue destruction releasing large amounts of nutrients from tissue cells, which enhanced the germination speed under this immunosuppresive regimen. The mild inflammation under RB6-8C5 treatment one day post infection and the absence of inflammation under cyclophosphamide treatment may not provide the same nutritional conditions leading to a delayed germination when compared to the cortisone acetate treatment. Another piece of evidence that supports the dependence on the number and functional integrity of neutrophils in the clearance of A. fumigatus is the observation that RB6-8C5 treatment renders mice highly susceptible to IA.