CONCENTRATION-DEPENDENT AND TIME-DEPENDENT UP-REGULATION AND RELEASE OF THE CYTOKINES MIP-2, KC, TNF, AND MIP-1-ALPHA IN RAT ALVEOLAR MACROPHAGES BY FUNGAL SPORES IMPLICATED IN AIRWAY INFLAMMATION

Inhalation of fungal spores has been shown to cause primary or seconda ry infection and respiratory inflammation and diseases such as allergi c alveolitis, atopic asthma, and organic dust toxic syndrome, which ar e rarely reported in the absence of predisposing factors. Biochemical and molecular markers of inflammation were measured in rat bronchial a lveolar lavage cells (> 95% macrophages) following stimulation with fu ngal spores isolated from pathogenic and nonpathogenic fungi that have been implicated in airway inflammation. The results of this study dem onstrate that mRNA transcripts for the C-X-C branch of the PF4 superfa mily are differentially upregulated over those of the C-C mediators in a time-and concentration-dependent manner. Macrophage inflammatory pr otein (MIP)-2 and KC were differentially upregulated over the acute ph ase inflammatory cytokines MIP-1 alpha and tumor necrosis factor-alpha (TNF-alpha) in rat alveolar macrophages stimulated with fungal spores from Aspergillus candidus, Aspergillus niger; Eurotium amstelodami, a nd Cladosporium cladosporioides. Spores from Aspergillus terreus and P enicillium spinulosum failed to stimulate an increase of any cytokine mRNA, whereas those from Aspergillus fumigatus stimulated the upregula tion of MIP-2, KC, TNF-alpha, and MIP-1 alpha mRNAs. Over time, A. fum igatus stimulated increasing KC production until 24 h, when production levels increased slightly, then leveled off when measurements ceased at 36 h. Latex spheres stimulated modest amounts of MIP-2 and transfor ming growth factor-beta only. These observations suggest that the infl ammatory cytokines MIP-2 and KC may be involved in the inflammation ar ising from the inhalation of fungal spores in a time-and concentration -dependent manner.