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. 2003 Aug;12(4):195–202. doi: 10.1080/09629350310001599620

Suppressive activity of macrolide antibiotics on nitric oxide production by lipopolysaccharide stimulation in mice.

Hajime Terao 1, Kazuhito Asano 1, Ken-ichi Kanai 1, Yoshiyuki Kyo 1, So Watanabe 1, Tadashi Hisamitsu 1, Harumi Suzaki 1
PMCID: PMC1781621  PMID: 14514469

Abstract

BACKGROUND: Low-dose and long-term administration of macrolide antibiotics into patients with chronic airway inflammatory diseases could favorably modify their clinical conditions. However, the therapeutic mode of action of macrolides is not well understood. Free oxygen radicals, including nitric oxide (NO), are well recognized as the important final effector molecules in the development and the maintenance of inflammatory diseases. PURPOSE: The influence of macrolide antibiotics on NO generation was examined in vivo. METHODS: Male ICR mice, 5 weeks of age, were orally administered with either roxithromycin, clarithromycin, azithromycin or josamycin once a day for 2-4 weeks. The mice were then injected intraperitoneally with 5.0 mg/kg lipopolysaccharide (LPS) and the plasma NO level was examined 6 h later. RESULTS: Although pre-treatment of mice with macrolide antibiotics for 2 weeks scarcely affected NO generation by LPS injection, the administration of macrolide antibiotics, except for josamycin, for 4 weeks significantly inhibited LPS-induced NO generation. The data in the present study also showed that pre-treatment of mice with macrolide antibiotics for 4 weeks significantly suppresses not only production of pro-inflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha, but also inducible nitric oxide synthase mRNA expressions, which are enhanced by LPS injection. CONCLUSION: These results strongly suggest that suppressive activity of macrolide antibiotics on NO generation in response to LPS stimulation in vivo may, in part, account for the clinical efficacy of macrolides on chronic inflammatory diseases.

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Selected References

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  1. Altschuler E. L. Azithromycin, the multidrug-resistant protein, and cystic fibrosis. Lancet. 1998 Apr 25;351(9111):1286–1286. doi: 10.1016/S0140-6736(05)79350-8. [DOI] [PubMed] [Google Scholar]
  2. Asano K., Kamakazu K., Hisamitsu T., Suzaki H. Modulation of Th2 type cytokine production from human peripheral blood leukocytes by a macrolide antibiotic, roxithromycin, in vitro. Int Immunopharmacol. 2001 Oct;1(11):1913–1921. doi: 10.1016/s1567-5769(01)00116-3. [DOI] [PubMed] [Google Scholar]
  3. Ianaro A., Ialenti A., Maffia P., Sautebin L., Rombolà L., Carnuccio R., Iuvone T., D'Acquisto F., Di Rosa M. Anti-inflammatory activity of macrolide antibiotics. J Pharmacol Exp Ther. 2000 Jan;292(1):156–163. [PubMed] [Google Scholar]
  4. Ichikawa Y., Koga H., Tanaka M., Nakamura M., Tokunaga N., Kaji M. Neutrophilia in bronchoalveolar lavage fluid of diffuse panbronchiolitis. Chest. 1990 Oct;98(4):917–923. doi: 10.1378/chest.98.4.917. [DOI] [PubMed] [Google Scholar]
  5. Iino Y., Toriyama M., Kudo K., Natori Y., Yuo A. Erythromycin inhibition of lipopolysaccharide-stimulated tumor necrosis factor alpha production by human monocytes in vitro. Ann Otol Rhinol Laryngol Suppl. 1992 Oct;157:16–20. doi: 10.1177/0003489492101s1005. [DOI] [PubMed] [Google Scholar]
  6. Jaffé A., Francis J., Rosenthal M., Bush A. Long-term azithromycin may improve lung function in children with cystic fibrosis. Lancet. 1998 Feb 7;351(9100):420–420. doi: 10.1016/S0140-6736(05)78360-4. [DOI] [PubMed] [Google Scholar]
  7. Keicho Naoto, Kudoh Shoji. Diffuse panbronchiolitis: role of macrolides in therapy. Am J Respir Med. 2002;1(2):119–131. doi: 10.1007/BF03256601. [DOI] [PubMed] [Google Scholar]
  8. Konno S., Adachi M., Asano K., Kawazoe T., Okamoto K., Takahashi T. Influences of roxithromycin on cell-mediated immune responses. Life Sci. 1992;51(10):PL107–PL112. doi: 10.1016/0024-3205(92)90493-9. [DOI] [PubMed] [Google Scholar]
  9. Kooy N. W., Royall J. A., Ye Y. Z., Kelly D. R., Beckman J. S. Evidence for in vivo peroxynitrite production in human acute lung injury. Am J Respir Crit Care Med. 1995 Apr;151(4):1250–1254. doi: 10.1164/ajrccm/151.4.1250. [DOI] [PubMed] [Google Scholar]
  10. Kunikata Tomonori, Miyazawa Tohru, Kanatsu Kenji, Kato Shinichi, Takeuchi Koji. Protective effect of thiaton, an antispasmodic drug, against indomethacin-induced intestinal damage in rats. Jpn J Pharmacol. 2002 Jan;88(1):45–54. doi: 10.1254/jjp.88.45. [DOI] [PubMed] [Google Scholar]
  11. Lundberg J. O., Farkas-Szallasi T., Weitzberg E., Rinder J., Lidholm J., Anggåard A., Hökfelt T., Lundberg J. M., Alving K. High nitric oxide production in human paranasal sinuses. Nat Med. 1995 Apr;1(4):370–373. doi: 10.1038/nm0495-370. [DOI] [PubMed] [Google Scholar]
  12. Mizoguchi H., Ogawa Y., Kanatsu K., Tanaka A., Kato S., Takeuchi K. Protective effect of rebamipide on indomethacin-induced intestinal damage in rats. J Gastroenterol Hepatol. 2001 Oct;16(10):1112–1119. doi: 10.1046/j.1440-1746.2001.02592.x. [DOI] [PubMed] [Google Scholar]
  13. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  14. Muranaka H., Suga M., Sato K., Nakagawa K., Akaike T., Okamoto T., Maeda H., Ando M. Superoxide scavenging activity of erythromycin-iron complex. Biochem Biophys Res Commun. 1997 Mar 6;232(1):183–187. doi: 10.1006/bbrc.1997.6182. [DOI] [PubMed] [Google Scholar]
  15. Palmer R. M., Bridge L., Foxwell N. A., Moncada S. The role of nitric oxide in endothelial cell damage and its inhibition by glucocorticoids. Br J Pharmacol. 1992 Jan;105(1):11–12. doi: 10.1111/j.1476-5381.1992.tb14202.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Suzaki H., Asano K., Ohki S., Kanai K., Mizutani T., Hisamitsu T. Suppressive activity of a macrolide antibiotic, roxithromycin, on pro-inflammatory cytokine production in vitro and in vivo. Mediators Inflamm. 1999;8(4-5):199–204. doi: 10.1080/09629359990351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Yermilov V., Rubio J., Ohshima H. Formation of 8-nitroguanine in DNA treated with peroxynitrite in vitro and its rapid removal from DNA by depurination. FEBS Lett. 1995 Dec 4;376(3):207–210. doi: 10.1016/0014-5793(95)01281-6. [DOI] [PubMed] [Google Scholar]
  18. Zoritch B. Nitric oxide and asthma. Arch Dis Child. 1995 Mar;72(3):259–262. doi: 10.1136/adc.72.3.259. [DOI] [PMC free article] [PubMed] [Google Scholar]

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