The in vivo function of murine granulocyte-macrophage colony-stimulati
ng factor (GM-CSF) was investigated in mice, carrying a null allele of
the GM-CSF gene, that were generated by gene targeting techniques in
embryonic stem cells. Although steady-state hematopoiesis was unimpair
ed in homozygous mutant animals, all animals developed the progressive
accumulation of surfactant lipids and proteins in the alveolar space,
the defining characteristic of the idiopathic human disorder pulmonar
y alveolar proteinosis. Extensive lymphoid hyperplasia associated with
lung airways and blood vessels was also found, yet no infectious agen
ts could be detected. These results demonstrate that GM-CSF is not an
essential growth factor for basal hematopoiesis and reveal an unexpect
ed, critical role for GM-CSF in pulmonary homeostasis.