title: Keratinocyte growth factor supports pulmonary innate immune defense through maintenance of alveolar antimicrobial protein levels and macrophage function.
abstract: Keratinocyte growth factor (KGF) is an epithelial mitogen that has been reported to protect the lungs from a variety of toxic and infectious insults. In prior studies we found that recombinant human KGF accelerates clearance of bacteria from the murine lung by augmenting the function of alveolar macrophages (AM). In this study we tested the hypothesis that endogenous KGF plays a role in the maintenance of innate pulmonary defense against gram-negative bacterial infections. KGF-deficient mice exhibited delayed clearance of Escherichia coli from the lungs, attenuated phagocytosis by AM, and decreased antimicrobial activity in bronchoalveolar lavage (BAL) fluid, due in part to reductions in levels of surfactant protein A, surfactant protein D, and lysozyme. These immune deficits were accompanied by lower alveolar type II epithelial cell counts and reduced alveolar type II epithelial cell expression of collectin and lysozyme genes on a per cell basis. No significant between-group differences were detected in selected inflammatory cytokines or BAL inflammatory cell populations at baseline or after bacterial challenge in the wild-type and KGF-deficient mice. A single intranasal dose of recombinant human KGF reversed defects in bacterial clearance, AM function, and BAL fluid antimicrobial activity. We conclude that KGF supports alveolar innate immune defense through maintenance of alveolar antimicrobial protein levels and functions of AM. Together these data demonstrate a role for endogenous KGF in maintenance of normal pulmonary innate immune function.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Gardner
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors.forename: Huixing
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Research, Shriners Hospitals for Children, Cincinnati, Ohio.
authors.forename: John G
authors.initials: JG
authors.lastname: Noel
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Ramser
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors.forename: Lori
authors.initials: L
authors.lastname: Pitstick
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Saito
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; and.
authors.forename: Nikolaos M
authors.initials: NM
authors.lastname: Nikolaidis
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; and frank.mccormack@uc.edu.
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D037222:Collectins / Q000235:genetics / Q000378:metabolism; D004927:Escherichia coli Infections / Q000276:immunology* / Q000378:metabolism; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000502:physiology*; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000382:microbiology; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009113:Muramidase / Q000235:genetics / Q000378:metabolism; D018410:Pneumonia, Bacterial / Q000276:immunology* / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000276:immunology / Q000378:metabolism / Q000382:microbiology
chemical_list: D037222:Collectins; D051523:Fibroblast Growth Factor 7; D009113:Muramidase
keywords: alveolar macrophages; collectins; innate defense; keratinocyte growth factor; lysozyme; pneumonia