title: Keratinocyte growth factor administration attenuates murine pulmonary mycobacterium tuberculosis infection through granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent macrophage activation and phagolysosome fusion.
abstract: Augmentation of innate immune defenses is an appealing adjunctive strategy for treatment of pulmonary Mycobacterium tuberculosis infections, especially those caused by drug-resistant strains. The effect of intranasal administration of keratinocyte growth factor (KGF), an epithelial mitogen and differentiation factor, on M. tuberculosis infection in mice was tested in prophylaxis, treatment, and rescue scenarios. Infection of C57BL6 mice with M. tuberculosis resulted in inoculum size-dependent weight loss and mortality. A single dose of KGF given 1 day prior to infection with 10(5) M. tuberculosis bacilli prevented weight loss and enhanced pulmonary mycobacterial clearance (compared with saline-pretreated mice) for up to 28 days. Similar effects were seen when KGF was delivered intranasally every third day for 15 days, but weight loss and bacillary growth resumed when KGF was withdrawn. For mice with a well established M. tuberculosis infection, KGF given every 3 days beginning on day 15 postinoculation was associated with reversal of weight loss and an increase in M. tuberculosis clearance. In in vitro co-culture experiments, M. tuberculosis-infected macrophages exposed to conditioned medium from KGF-treated alveolar type II cell (MLE-15) monolayers exhibited enhanced GM-CSF-dependent killing through mechanisms that included promotion of phagolysosome fusion and induction of nitric oxide. Alveolar macrophages from KGF-treated mice also exhibited enhanced GM-CSF-dependent phagolysosomal fusion. These results provide evidence that administration of KGF promotes M. tuberculosis clearance through GM-CSF-dependent mechanisms and enhances host defense against M. tuberculosis infection.
authors.affiliation: From the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267 and.
authors.forename: Rajamouli
authors.initials: R
authors.lastname: Pasula
authors.affiliation: the Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio 43210.
authors.forename: Abul K
authors.initials: AK
authors.lastname: Azad
authors.affiliation: From the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267 and.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Gardner
authors.affiliation: the Center for Microbial Interface Biology, Department of Microbial Infection and Immunity, Ohio State University, Columbus, Ohio 43210.
authors.forename: Larry S
authors.initials: LS
authors.lastname: Schlesinger
authors.affiliation: From the Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, University of Cincinnati, Cincinnati, Ohio 45267 and frank.mccormack@uc.edu.
authors.forename: Francis X
authors.initials: FX
authors.lastname: McCormack
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000627:therapeutic use*; D002478:Cells, Cultured; D005260:Female; D051523:Fibroblast Growth Factor 7 / Q000627:therapeutic use*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000276:immunology*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D008262:Macrophage Activation / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000382:microbiology; D051379:Mice; D008810:Mice, Inbred C57BL; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D010588:Phagosomes / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000276:immunology / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D051523:Fibroblast Growth Factor 7; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
keywords: Cell Activation; Epithelium; Growth Factor; Innate Immunity; Keratinocyte; Lung; Macrophage; Mycobacterium tuberculosis; Rodent