GM-CSF and the impaired pulmonary innate immune response following hyperoxic stress.
We have previously demonstrated that mice exposed to sublethal hyperoxia (an atmosphere of >95% oxygen for 4 days, followed by return to room air) have significantly impaired pulmonary innate immune response. Alveolar macrophages (AM) from hyperoxia-exposed mice exhibit significantly diminished antimicrobial activity and markedly reduced production of inflammatory cytokines in response to stimulation with LPS compared with AM from control mice in normoxia. As a consequence of these defects, mice exposed to sublethal hyperoxia are more susceptible to lethal pneumonia with Klebsiella pneumoniae than control mice. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a growth factor produced by normal pulmonary alveolar epithelial cells that is critically involved in maintenance of normal AM function. We now report that sublethal hyperoxia in vivo leads to greatly reduced alveolar epithelial cell GM-CSF expression. Systemic treatment of mice with recombinant murine GM-CSF during hyperoxia exposure preserved AM function, as indicated by cell surface Toll-like receptor 4 expression and by inflammatory cytokine secretion following stimulation with LPS ex vivo. Treatment of hyperoxic mice with GM-CSF significantly reduced lung bacterial burden following intratracheal inoculation with K. pneumoniae, returning lung bacterial colony-forming units to the level of normoxic controls. These data point to a critical role for continuous GM-CSF activity in the lung in maintenance of normal AM function and demonstrate that lung injury due to hyperoxic stress results in significant impairment in pulmonary innate immunity through suppression of alveolar epithelial cell GM-CSF expression.
Baleeiro
Carlos E O
CE
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, USA.
Christensen
Paul J
PJ
Morris
Susan B
SB
Mendez
Michael P
MP
Wilcoxen
Steven E
SE
Paine
Robert
R
D000818:Animals; D017931:DNA Primers; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000494:pharmacology*; D018496:Hyperoxia / Q000503:physiopathology*; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D016178:Granulocyte-Macrophage Colony-Stimulating Factor