title: Nitric oxide is required for effective innate immunity against Klebsiella pneumoniae.
abstract: Nitric oxide (NO) has been associated with protection against various parasitic and viral infections and may play a similar role in bacterial infections. We studied the role of NO in host defense against Klebsiella pneumoniae infection in the lung. Initial studies demonstrated a time-dependent increase in NO production of the lungs of CBA/J mice following the intratracheal administration of K. pneumoniae (7 x 10(2) CFU). To assess the role of NO in Klebsiella pneumonia, mice were treated intraperitoneally with either L-NAME (N-omega-nitro-L-arginine methylester), a competitive inhibitor of NO synthesis, or D-NAME, an inert enantiomer. The treatment of Klebsiella-infected mice with L-NAME resulted in a 10- and 46-fold increase in K. pneumoniae CFU in lungs and blood, respectively, at 48 h post-K. pneumoniae inoculation compared to treatment of mice with D-NAME. In addition, a greater-than-twofold increase in mortality was evident in L-NAME-treated mice compared to the mortality in control animals. No significant difference in bronchoalveolar lavage inflammatory cell profiles was noted between L-NAME- and D-NAME-treated mice with Klebsiella pneumonia. Interestingly, increased levels of tumor necrosis factor, gamma interferon, macrophage inflammatory protein 1alpha (MIP-1alpha), and MIP-2 mRNA and protein were noted in infected mice treated with L-NAME compared to the levels in mice treated with D-NAME. Importantly, the in vitro incubation of murine alveolar macrophages with L-NAME, but not with D-NAME, resulted in a significant impairment in both the phagocytosis and killing of K. pneumoniae. In total, these results suggest that NO plays a critical role in antibacterial host defense against K. pneumoniae, in part by regulating macrophage phagocytic and microbicidal activity.
authors.affiliation: Department of Medicine, University of Michigan Medical School, Ann Arbor 48109-0360, USA.
authors.forename: W C
authors.initials: WC
authors.lastname: Tsai
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
authors.forename: D A
authors.initials: DA
authors.lastname: Zisman
authors.forename: J M
authors.initials: JM
authors.lastname: Wilkowski
authors.forename: K A
authors.initials: KA
authors.lastname: Bucknell
authors.forename: G H
authors.initials: GH
authors.lastname: Chen
authors.forename: T J
authors.initials: TJ
authors.lastname: Standiford
mesh_terms: D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002478:Cells, Cultured; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D015169:Colony Count, Microbial; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000032:analysis / Q000276:immunology; D007710:Klebsiella Infections / Q000097:blood / Q000276:immunology* / Q000378:metabolism*; D007711:Klebsiella pneumoniae; D008168:Lung / Q000378:metabolism / Q000382:microbiology; D019402:Macrophage Inflammatory Proteins / Q000032:analysis / Q000276:immunology; D016676:Macrophages, Alveolar / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D015846:Monokines / Q000032:analysis / Q000235:genetics / Q000276:immunology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology*; D009573:Nitrites / Q000032:analysis / Q000378:metabolism; D010587:Phagocytosis / Q000187:drug effects; D018410:Pneumonia, Bacterial / Q000097:blood / Q000276:immunology* / Q000378:metabolism*; D011506:Proteins / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis; D013237:Stereoisomerism; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology
chemical_list: D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054426:Chemokine CXCL2; D004791:Enzyme Inhibitors; D019402:Macrophage Inflammatory Proteins; D015846:Monokines; D009573:Nitrites; D011506:Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D007371:Interferon-gamma; D019331:NG-Nitroarginine Methyl Ester