The effects of granulocyte colony-stimulating factor and neutrophil recruitment on the pulmonary chemokine response to intratracheal endotoxin

Although G-CSF has been shown to increase neutrophil (polymorphonuclear leu kocyte, PMN) recruitment into the lung during pulmonary infection, relative ly little is known about the local chemokine profiles associated with this enhanced PMN delivery. We investigated the effects of G-CSF and PMN recruit ment on the pulmonary chemokine response to intratracheal LPS. Rats pretrea ted twice daily for 2 days with an s.c. injection of G-CSF (50 mug/kg) were sacrificed at either 90 min or 4 h after intratracheal LPS (100 mug) chall enge. Pulmonary recruitment of PMNs was not observed at 90 min post LPS cha llenge. Macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neut rophil chemoattractant (CINC) concentrations in bronchoalveolar lavage (BAL ) fluid were similar in animals pretreated with or without G-CSF at this ti me. G-CSF pretreatment enhanced pulmonary recruitment of PMNs (5-fold) and greatly reduced MIP-2 and CINC levels in BAL fluid at 4 h after LPS challen ge. In vitro, the presence of MIP-2 and CINC after LPS stimulation of alveo lar macrophages was decreased by coculturing with circulating PMNs but not G-CSF. G-CSF had no direct effect on LPS-induced MIP-2 and CINC mRNA expres sion by alveolar macrophages, Pulmonary recruited PMNs showed a significant increase in cell-associated MIP-2 and CINC, Cell-associated MIP-2 and CINC of circulating PMNs were markedly increased after exposure of these cells to the BAL fluid of LPS-challenged lungs. These data suggest that recruited PMNs are important cells in modulating the local chemokine response. G-CSF augments PMN recruitment and, thereby, lowers local chemokine levels, whic h may be one mechanism resulting in the subsidence of the host proinflammat ory response.