(D, E, F): Early germinating conidia were observed in the inflammatory infiltrates either free or in the cytoplasm of alveolar macrophages (arrowheads). Note that the conidia and hyphae were less mature than under cortisone acetate treatment (Figure.
6). A, C: HE staining; B, D, E, F: GMS staining. The late stage (three days post infection) of IA induced by transient neutrophil depletion (Figure 11) was characterised by a FDA approval PARP inhibitor multifocal inflammatory lesion, centered on bronchi and bronchioles but extending to alveoli and blood vessels as well (Figure 11A). The lesions were extensive, with large areas of necrosis and vascular involvement that was more pronounced than in cortisone acetate-treated mice (Table 1). Mature septated fungal hyphae STI571 in vivo were observed infiltrating bronchiolar and alveolar spaces as well as interstitial tissue (Figure 11B, D). Hyphae were more numerous than in cortisone acetate-treated mice and infiltrated the pulmonary parenchyma more readily (Figure 11A, B). The inflammatory infiltrate was predominately composed of mononuclear cells (monocytes/macrophages and lymphocytes and plasma cells) (Figure 10C). Individual lesions measured up to 500 μm2 in area and accounted 18.9 ± 2.8% of the
total lung section surface (Table 1), which is even higher than the area affected under cortisone acetate treatment. Figure 11 In the late stage after RB6-8C5 treatment, macrophages and recruited monocytes were unable to prevent fungal lung colonisation. (A): Multifocal large inflammatory infiltrates centred on bronchioles but GSI-IX mouse Urease extending to alveoli and blood vessels (arrowheads). (B): Fungi displayed a high infiltrative potential with a marked extension to alveoli (arrowheads). (C): Inflammatory infiltrates were composed of mononucleated cells; mainly macrophages (inlay). (D): Hyphae were mature and displayed a high invasive potential. A, C: HE staining; B, D: GMS staining.
Taken together, these data indicate that the recruitment of mononuclear cells, in the absence of neutrophils, is insufficient to prevent conidial germination, hyphal outgrowth and tissue infiltration. It is likely that the severe vascular and parenchymal lesions observed in RB6-8C5-treated mice prevented the development of high bioluminescent signals in vivo. This is most likely due to hypoxia resulting from the pulmonary parenchyma destruction, which was even more severe than under cortisone acetate treatment. Cyclophosphamide treatment Treatment with cyclophosphamide was expected to cause severe neutropenia accompanied by a reduction of monocytes. However, resident alveolar macrophages were not expected to be affected by this treatment. Bioluminescence imaging revealed that cyclophosphamide treatment resulted in a delayed (apparent at day 2 to day 3 post-infection), but steadily increasing bioluminescence signal until mice succumbed to progressive disease (Figure 1C and Figure 2 inlet).