Impaired functional activity of alveolar macrophages from GM-CSF-deficientmice

We hypothesized that pulmonary granulocyte-macrophage colony-stimulating fa ctor (GM-CSF) is critically involved in determining the functional capabili ties of alveolar macrophages (AM) for host defense. To test this hypothesis , cells were collected by lung lavage from GM-CSF mutant mice [GM(-/-)] and C57BL/6 wild-type mice. GM(-/-) mice yielded almost 4-fold more AM than wi ld-type mice. The percentage of cells positive for the beta (2)-integrins C D11a and CD11c was reduced significantly in GM(-/-) AM compared with wild-t ype cells, whereas expression of CD11b was similar in the two groups. The p hagocytic activity of GM(-/-) AM for FITC-labeled microspheres was impaired significantly compared with that of wild-type AM both in vitro and in vivo (after intratracheal inoculation with FITC-labeled beads). Stimulated secr etion of tumor necrosis factor-alpha (TNF-alpha) and leukotrienes by AM fro m the GM(-/-) mice was greatly reduced compared with wild-type AM, whereas secretion of monocyte chemoattractant protein-1 was increased. Transgenic e xpression of GM-CSF exclusively in the lungs of GM(-/-) mice resulted in AM with normal or supranormal expression of CD11a and CD11c, phagocytic activ ity, and TNF-alpha secretion. Thus, in the absence of GMCSF, AM functional capabilities for host defense were significantly impaired but were restored by lung-specific expression of GM-CSF.