Skip to main content
NCBI home page
Infection and Immunity logoLink to Infection and Immunity
. 1997 May;65(5):1870–1875. doi: 10.1128/iai.65.5.1870-1875.1997

Nitric oxide is required for effective innate immunity against Klebsiella pneumoniae.

W C Tsai 1, R M Strieter 1, D A Zisman 1, J M Wilkowski 1, K A Bucknell 1, G H Chen 1, T J Standiford 1
PMCID: PMC175233  PMID: 9125574

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.

Full Text

The Full Text of this article is available as a PDF (246.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Albina J. E., Cui S., Mateo R. B., Reichner J. S. Nitric oxide-mediated apoptosis in murine peritoneal macrophages. J Immunol. 1993 Jun 1;150(11):5080–5085. [PubMed] [Google Scholar]
  2. Alspaugh J. A., Granger D. L. Inhibition of Cryptococcus neoformans replication by nitrogen oxides supports the role of these molecules as effectors of macrophage-mediated cytostasis. Infect Immun. 1991 Jul;59(7):2291–2296. doi: 10.1128/iai.59.7.2291-2296.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bakker-Woudenberg I. A., Lokerse A. F., ten Kate M. T., Mouton J. W., Woodle M. C., Storm G. Liposomes with prolonged blood circulation and selective localization in Klebsiella pneumoniae-infected lung tissue. J Infect Dis. 1993 Jul;168(1):164–171. doi: 10.1093/infdis/168.1.164. [DOI] [PubMed] [Google Scholar]
  4. Bi Z., Reiss C. S. Inhibition of vesicular stomatitis virus infection by nitric oxide. J Virol. 1995 Apr;69(4):2208–2213. doi: 10.1128/jvi.69.4.2208-2213.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brieland J. K., Remick D. G., Freeman P. T., Hurley M. C., Fantone J. C., Engleberg N. C. In vivo regulation of replicative Legionella pneumophila lung infection by endogenous tumor necrosis factor alpha and nitric oxide. Infect Immun. 1995 Sep;63(9):3253–3258. doi: 10.1128/iai.63.9.3253-3258.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Campbell G. D. Overview of community-acquired pneumonia. Prognosis and clinical features. Med Clin North Am. 1994 Sep;78(5):1035–1048. doi: 10.1016/s0025-7125(16)30118-3. [DOI] [PubMed] [Google Scholar]
  7. Corbett J. A., McDaniel M. L. Does nitric oxide mediate autoimmune destruction of beta-cells? Possible therapeutic interventions in IDDM. Diabetes. 1992 Aug;41(8):897–903. doi: 10.2337/diab.41.8.897. [DOI] [PubMed] [Google Scholar]
  8. Deitch E. A., Haskel Y., Cruz N., Xu D., Kvietys P. R. Caco-2 and IEC-18 intestinal epithelial cells exert bactericidal activity through an oxidant-dependent pathway. Shock. 1995 Nov;4(5):345–350. doi: 10.1097/00024382-199511000-00006. [DOI] [PubMed] [Google Scholar]
  9. Drevets D. A., Canono B. P., Leenen P. J., Campbell P. A. Gentamicin kills intracellular Listeria monocytogenes. Infect Immun. 1994 Jun;62(6):2222–2228. doi: 10.1128/iai.62.6.2222-2228.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Elferink J. G., VanUffelen B. E. The role of cyclic nucleotides in neutrophil migration. Gen Pharmacol. 1996 Mar;27(2):387–393. doi: 10.1016/0306-3623(95)00070-4. [DOI] [PubMed] [Google Scholar]
  11. Fierro I. M., Barja-Fidalgo C., Cunha F. Q., Ferreira S. H. The involvement of nitric oxide in the anti-Candida albicans activity of rat neutrophils. Immunology. 1996 Oct;89(2):295–300. doi: 10.1046/j.1365-2567.1996.d01-742.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fukushima T., Sekizawa K., Yamaya M., Okinaga S., Satoh M., Sasaki H. Viral respiratory infection increases alveolar macrophage cytoplasmic motility in rats: role of NO. Am J Physiol. 1995 Mar;268(3 Pt 1):L399–L406. doi: 10.1152/ajplung.1995.268.3.L399. [DOI] [PubMed] [Google Scholar]
  13. Garside P., Hutton A. K., Severn A., Liew F. Y., Mowat A. M. Nitric oxide mediates intestinal pathology in graft-vs.-host disease. Eur J Immunol. 1992 Aug;22(8):2141–2145. doi: 10.1002/eji.1830220827. [DOI] [PubMed] [Google Scholar]
  14. Gosselin D., DeSanctis J., Boulé M., Skamene E., Matouk C., Radzioch D. Role of tumor necrosis factor alpha in innate resistance to mouse pulmonary infection with Pseudomonas aeruginosa. Infect Immun. 1995 Sep;63(9):3272–3278. doi: 10.1128/iai.63.9.3272-3278.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Greenberger M. J., Strieter R. M., Kunkel S. L., Danforth J. M., Goodman R. E., Standiford T. J. Neutralization of IL-10 increases survival in a murine model of Klebsiella pneumonia. J Immunol. 1995 Jul 15;155(2):722–729. [PubMed] [Google Scholar]
  16. Greenberger M. J., Strieter R. M., Kunkel S. L., Danforth J. M., Laichalk L. L., McGillicuddy D. C., Standiford T. J. Neutralization of macrophage inflammatory protein-2 attenuates neutrophil recruitment and bacterial clearance in murine Klebsiella pneumonia. J Infect Dis. 1996 Jan;173(1):159–165. doi: 10.1093/infdis/173.1.159. [DOI] [PubMed] [Google Scholar]
  17. Hinder F., Booke M., Traber L. D., Matsumoto N., Nishida K., Rogers S., Traber D. L. Nitric oxide synthase inhibition during experimental sepsis improves renal excretory function in the presence of chronically increased atrial natriuretic peptide. Crit Care Med. 1996 Jan;24(1):131–136. doi: 10.1097/00003246-199601000-00022. [DOI] [PubMed] [Google Scholar]
  18. Kolls J. K., Nelson S., Summer W. R. Recombinant cytokines and pulmonary host defense. Am J Med Sci. 1993 Nov;306(5):330–335. doi: 10.1097/00000441-199311000-00012. [DOI] [PubMed] [Google Scholar]
  19. Kubes P., Suzuki M., Granger D. N. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4651–4655. doi: 10.1073/pnas.88.11.4651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Liew F. Y., Cox F. E. Nonspecific defence mechanism: the role of nitric oxide. Immunol Today. 1991 Mar;12(3):A17–A21. doi: 10.1016/S0167-5699(05)80006-4. [DOI] [PubMed] [Google Scholar]
  21. Liew F. Y. Interactions between cytokines and nitric oxide. Adv Neuroimmunol. 1995;5(2):201–209. doi: 10.1016/0960-5428(95)00009-q. [DOI] [PubMed] [Google Scholar]
  22. Liew F. Y., Li Y., Moss D., Parkinson C., Rogers M. V., Moncada S. Resistance to Leishmania major infection correlates with the induction of nitric oxide synthase in murine macrophages. Eur J Immunol. 1991 Dec;21(12):3009–3014. doi: 10.1002/eji.1830211216. [DOI] [PubMed] [Google Scholar]
  23. Liew F. Y. Regulation of nitric oxide synthesis in infectious and autoimmune diseases. Immunol Lett. 1994 Dec;43(1-2):95–98. doi: 10.1016/0165-2478(94)00157-x. [DOI] [PubMed] [Google Scholar]
  24. Moncada S., Palmer R. M., Higgs E. A. Biosynthesis of nitric oxide from L-arginine. A pathway for the regulation of cell function and communication. Biochem Pharmacol. 1989 Jun 1;38(11):1709–1715. doi: 10.1016/0006-2952(89)90403-6. [DOI] [PubMed] [Google Scholar]
  25. Orens J. B., Lukacs N. W., Kunkel S. L., Burdick M. D., Wilke C. A., Walz A., Strieter R. M. Regulation of chemokine production by the oxidative metabolism of L-arginine in a human mixed lymphocyte reaction. Cell Immunol. 1994 Jun;156(1):95–101. doi: 10.1006/cimm.1994.1155. [DOI] [PubMed] [Google Scholar]
  26. Petray P., Castaños-Velez E., Grinstein S., Orn A., Rottenberg M. E. Role of nitric oxide in resistance and histopathology during experimental infection with Trypanosoma cruzi. Immunol Lett. 1995 Jul-Aug;47(1-2):121–126. doi: 10.1016/0165-2478(95)00083-h. [DOI] [PubMed] [Google Scholar]
  27. Shi Y., Li H. Q., Shen C. K., Wang J. H., Pan J., Qin S. W., Liu R. Association between protective efficacy of antibodies to tumor necrosis factor and suppression of nitric oxide production in neonatal rats with fatal infection. Pediatr Res. 1993 Sep;34(3):345–348. doi: 10.1203/00006450-199309000-00021. [DOI] [PubMed] [Google Scholar]
  28. Stamler J. S., Singel D. J., Loscalzo J. Biochemistry of nitric oxide and its redox-activated forms. Science. 1992 Dec 18;258(5090):1898–1902. doi: 10.1126/science.1281928. [DOI] [PubMed] [Google Scholar]
  29. Taylor-Robinson A. W., Phillips R. S., Severn A., Moncada S., Liew F. Y. The role of TH1 and TH2 cells in a rodent malaria infection. Science. 1993 Jun 25;260(5116):1931–1934. doi: 10.1126/science.8100366. [DOI] [PubMed] [Google Scholar]
  30. Toews G. B., Gross G. N., Pierce A. K. The relationship of inoculum size to lung bacterial clearance and phagocytic cell response in mice. Am Rev Respir Dis. 1979 Sep;120(3):559–566. doi: 10.1164/arrd.1979.120.3.559. [DOI] [PubMed] [Google Scholar]
  31. VanOtteren G. M., Standiford T. J., Kunkel S. L., Danforth J. M., Burdick M. D., Abruzzo L. V., Strieter R. M. Expression and regulation of macrophage inflammatory protein-1 alpha by murine alveolar and peritoneal macrophages. Am J Respir Cell Mol Biol. 1994 Jan;10(1):8–15. doi: 10.1165/ajrcmb.10.1.8292385. [DOI] [PubMed] [Google Scholar]
  32. Wang Y. X., Poon C. I., Pang C. C. Vascular pharmacodynamics of NG-nitro-L-arginine methyl ester in vitro and in vivo. J Pharmacol Exp Ther. 1993 Dec;267(3):1091–1099. [PubMed] [Google Scholar]

Articles from Infection and Immunity are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES