Pulmonary macrophages play a crucial role in the defense of inhaled pathogens. We characterized functional properties of alveolar (AM) and interstitial (IM) macrophages from rats. AM exhibited a pronounced microbicidal capacity as shown by an elevated production of reactive oxygen intermediates (ROI), nitric oxide (NO), tumor necrosis factor (TNF)-alpha, and tumor cytotoxicity when compared with IM. In contrast, IM were superior to AM regarding mechanisms mainly involved in the induction and maintenance of specific immune reactions (major histocompatibility complex [MHC] class II expression, interleukin [IL]-1 and IL-6). In this line, we were interested in whether the microbicidal potential of AM could be augmented by treating Lewis rats with rat recombinant interferon (IFN)-gamma (5 x 10(2) to 1 x 10(5) U/animal) intratracheally, avoiding infection of interstitial lung macrophages or other organ-associated macrophages. The pulmonary cytokine application resulted in an activation of AM when macrophages from IFN-treated animals were compared with control macrophages from saline-treated rats 18 h after the treatment: (1) mediator release (ROI, NO, TNF-alpha, IL-6), (2) tumoricidal activity; (3) dose-dependent increase of MHC class II expression. The local immunomodulation enhanced the resistance of normal and immunosuppressed rats against respiratory infections with Listeria monocytogenes. Taken together, local activation of lung macrophages is a feasible therapeutic strategy against pulmonary infections.