The Effects of Granulocyte Colony-Stimulating Factor and Neutrophil Recruitment on the Pulmonary Chemokine Response to Intratracheal Endotoxin

• Published in: The Journal of immunology (1950) Vol. 166; no. 1; pp. 458 - 465
• Main Authors: Zhang, Ping, Bagby, Gregory J, Kolls, Jay K, Welsh, David A, Summer, Warren R, Andresen, Jeff, Nelson, Steve
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.01.2001
• Subjects: Animals; Cells, Cultured; Chemokine CXCL1; Chemokine CXCL2; Chemokines - antagonists & inhibitors; Chemokines - biosynthesis; Chemokines - genetics; Chemokines - metabolism; Chemokines, CXC - antagonists & inhibitors; Chemokines, CXC - biosynthesis; Chemokines, CXC - genetics; Chemokines, CXC - metabolism; Chemotactic Factors - antagonists & inhibitors; Chemotactic Factors - biosynthesis; Chemotactic Factors - genetics; Chemotactic Factors - metabolism; CINC protein; Coculture Techniques; Granulocyte Colony-Stimulating Factor - administration & dosage; Granulocyte Colony-Stimulating Factor - pharmacology; Growth Substances - biosynthesis; Growth Substances - genetics; Growth Substances - metabolism; Injections, Subcutaneous; Intercellular Signaling Peptides and Proteins; Intubation, Intratracheal; Lipopolysaccharides - administration & dosage; Lung - immunology; Lung - metabolism; macrophage inflammatory protein 2; Macrophages, Alveolar - immunology; Macrophages, Alveolar - metabolism; Male; Neutrophil Infiltration - immunology; Neutrophils - immunology; Neutrophils - metabolism; Rats; Rats, Sprague-Dawley; RNA, Messenger - biosynthesis
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.166.1.458

Although G-CSF has been shown to increase neutrophil (polymorphonuclear leukocyte, PMN) recruitment into the lung during pulmonary infection, relatively little is known about the local chemokine profiles associated with this enhanced PMN delivery. We investigated the effects of G-CSF and PMN recruitment on the pulmonary chemokine response to intratracheal LPS. Rats pretreated twice daily for 2 days with an s.c. injection of G-CSF (50 microg/kg) were sacrificed at either 90 min or 4 h after intratracheal LPS (100 microg) challenge. Pulmonary recruitment of PMNs was not observed at 90 min post LPS challenge. Macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) concentrations in bronchoalveolar lavage (BAL) fluid were similar in animals pretreated with or without G-CSF at this time. 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 challenge. In vitro, the presence of MIP-2 and CINC after LPS stimulation of alveolar 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 expression 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, which may be one mechanism resulting in the subsidence of the host proinflammatory response.