OBJECTIVE The process by which hematopoietic tissues respond to a pulmonary infection remains poorly understood. This study investigated the potential role of lung-derived granulopoietic cytokines in facilitating this response. METHODS Laboratory investigation. METHODS University laboratory. METHODS Male Balb/c mice. METHODS Mice were challenged with intratracheal Escherichia coli or granulocyte colony-stimulating factor (G-CSF). Bone marrow cells were isolated from normal mice and treated in vitro with G-CSF. RESULTS Bronchoalveolar lavage fluid concentrations of G-CSF, macrophage inflammatory protein-2, and keratinocyte-derived chemokine were elevated 3 and 6 hrs after intratracheal E. coli. The increases in intrapulmonary G-CSF and keratinocyte-derived chemokine were associated with increases of their concentrations in the plasma. The numbers of granulocyte-macrophage colony forming units in bone marrow, spleen, and blood were increased 48 hrs after intratracheal E. coli or G-CSF. In addition, plasma G-CSF and the number of progenitor cells (lin-ckit+Sca-1(-)) in the blood were increased at 30 mins and 48 hrs, respectively, following intratracheal G-CSF. Signal transducer and activator of transcription-3 in bone marrow cells was activated following intratracheal E. coli or G-CSF in addition to activation by in vitro G-CSF stimulation. CONCLUSIONS During pulmonary infection, locally produced cytokines enter the circulation and may play an important role in initiating a granulopoietic response.