title: Plasma gelsolin improves lung host defense against pneumonia by enhancing macrophage NOS3 function.
abstract: Plasma gelsolin (pGSN) functions as part of the "extracellular actin-scavenging system," but its potential to improve host defense against infection has not been studied. In a mouse model of primary pneumococcal pneumonia, recombinant human pGSN (rhu-pGSN) caused enhanced bacterial clearance, reduced acute inflammation, and improved survival. In vitro, rhu-pGSN rapidly improved lung macrophage uptake and killing of bacteria (Streptococcus pneumoniae, Escherichia coli, and Francisella tularensis). pGSN triggers activating phosphorylation (Ser(1177)) of macrophage nitric oxide synthase type III (NOS3), an enzyme with important bactericidal functions in lung macrophages. rhu-pGSN failed to enhance bacterial killing by NOS3(-/-) macrophages in vitro or bacterial clearance in NOS3(-/-) mice in vivo. Prophylaxis with immunomodulators may be especially relevant for patients at risk for secondary bacterial pneumonia, e.g., after influenza. Treatment of mice with pGSN challenged with pneumococci on postinfluenza day 7 (the peak of enhanced susceptibility to secondary infection) caused a ∼15-fold improvement in bacterial clearance, reduced acute neutrophilic inflammation, and markedly improved survival, even without antibiotic therapy. pGSN is a potential immunomodulator for improving lung host defense against primary and secondary bacterial pneumonia.
authors.affiliation: Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts;
authors.forename: Zhiping
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts; Department of Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung City, Taiwan; and Chang-Gung University College of Medicine, Tao-Yuan City, Taiwan.
authors.forename: Terry Ting-Yu
authors.initials: TT
authors.lastname: Chiou
authors.affiliation: Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts;
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Stossel
authors.affiliation: Department of Environmental Health, Harvard T. H. Chan School of Public Health, Boston, Massachusetts; lkobzik@hsph.harvard.edu.
authors.forename: Lester
authors.initials: L
authors.lastname: Kobzik
mesh_terms: D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004926:Escherichia coli / Q000276:immunology; D005604:Francisella tularensis / Q000276:immunology; D018260:Gelsolin / Q000097:blood / Q000494:pharmacology*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology; D008168:Lung / Q000382:microbiology*; D016676:Macrophages, Alveolar / Q000201:enzymology / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000276:immunology*; D009976:Orthomyxoviridae Infections / Q000276:immunology; D010587:Phagocytosis / Q000276:immunology; D011018:Pneumonia, Pneumococcal / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control; D011994:Recombinant Proteins / Q000494:pharmacology; D013296:Streptococcus pneumoniae / Q000276:immunology
chemical_list: D018260:Gelsolin; D011994:Recombinant Proteins; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse
keywords: gelsolin; innate immunity; lung macrophages; nitric oxide; pneumonia