title: Keratinocyte growth factor augments pulmonary innate immunity through epithelium-driven, GM-CSF-dependent paracrine activation of alveolar macrophages.
abstract: Keratinocyte growth factor (KGF) is an epithelial mitogen that has been reported to protect the lungs from a variety of insults. In this study, we tested the hypothesis that KGF augments pulmonary host defense. We found that a single dose of intrapulmonary KGF enhanced the clearance of Escherichia coli or Pseudomonas aeruginosa instilled into the lungs 24 h later. KGF augmented the recruitment, phagocytic activity, and oxidant responses of alveolar macrophages, including lipopolysaccharide-stimulated nitric oxide release and zymosan-induced superoxide production. Less robust alveolar macrophage recruitment and activation was observed in mice treated with intraperitoneal KGF. KGF treatment was associated with increased levels of MIP1γ, LIX, VCAM, IGFBP-6, and GM-CSF in the bronchoalveolar lavage fluid. Of these, only GM-CSF recapitulated in vitro the macrophage activation phenotype seen in the KGF-treated animals. The KGF-stimulated increase in GM-CSF levels in lung tissue and alveolar lining fluid arose from the epithelium, peaked within 1 h, and was associated with STAT5 phosphorylation in alveolar macrophages, consistent with epithelium-driven paracrine activation of macrophage signaling through the KGF receptor/GM-CSF/GM-CSF receptor/JAK-STAT axis. Enhanced bacterial clearance did not occur in response to KGF administration in GM-CSF(-/-) mice, or in mice treated with a neutralizing antibody to GM-CSF. We conclude that KGF enhances alveolar host defense through GM-CSF-stimulated macrophage activation. KGF administration may constitute a promising therapeutic strategy to augment innate immune defenses in refractory pulmonary infections.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Children's Hospital Medical Center, The University of Cincinnati, Cincinnati, Ohio 45267-0564, USA.
authors.forename: Huixing
authors.initials: H
authors.lastname: Wu
authors.forename: Takuji
authors.initials: T
authors.lastname: Suzuki
authors.forename: Brenna
authors.initials: B
authors.lastname: Carey
authors.forename: Bruce C
authors.initials: BC
authors.lastname: Trapnell
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
mesh_terms: D000818:Animals; D004848:Epithelium / Q000276:immunology; D051523:Fibroblast Growth Factor 7 / Q000008:administration & dosage / Q000276:immunology / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D007113:Immunity, Innate; D008168:Lung / Q000276:immunology*; D008262:Macrophage Activation / Q000187:drug effects* / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D019899:Paracrine Communication / Q000276:immunology*
chemical_list: D051523:Fibroblast Growth Factor 7; D016178:Granulocyte-Macrophage Colony-Stimulating Factor