Skip to main content
Mediators of Inflammation logoLink to Mediators of Inflammation
. 2004 Apr;13(2):111–117. doi: 10.1080/09629350410001688495

Anti-inflammatory and immunomodulating effects of clarithromycin in patients with cystic fibrosis lung disease.

Alexander L Pukhalsky 1, Galina V Shmarina 1, Nikolai I Kapranov 1, Svetlana N Kokarovtseva 1, Daria Pukhalskaya 1, Natalia J Kashirskaja 1
PMCID: PMC1781547  PMID: 15203552

Abstract

BACKGROUND AND AIM: Macrolide antibiotics are widely used in the treatment of suppurative lung diseases including cystic fibrosis (CF), the most common inherited fatal disease in the Caucasian population. This condition is characterized by secondary Pseudomonas infection resulting in neutrophil infiltration within the airways. The aim of the study was to investigate the evolution of inflammatory process in CF patients receiving long-term clarithromycin therapy. METHODS: Twenty-seven CF patients (mean age, 12 years) were enrolled into the study. Beside the basic therapy the patients were treated with clarithromycin at a dose of 250 mg every other day orally. All patients were routinely examined every 3 months. Blood and sputum were collected before clarithromycin treatment and then again 3, 6 and 12 months after the drug prescription. Cytokine concentrations (tumor necrosis factor-alpha, interleukin-8, interleukin-4, interferon-gamma) in the sputum and plasma were assayed. Peripheral blood lymphocyte response to phytohemagglutinin was also evaluated. RESULTS: Clarithromycin treatment resulted in a marked reduction of the cytokine levels both in the sputum and plasma specimens. At the same time, the interferon-gamma/interleukin-4 ratio has been significantly elevated. In addition, a sustained increase of peripheral blood lymphocyte response to phytohemagglutinin was demonstrated. These changes were associated with a significant improvement of the lung function. CONCLUSIONS: The beneficial effect of the prolonged treatment of CF patients with a 14-membered ring macrolide antibiotic clarithromycin seems to be associated not only with down-regulation of the inflammatory response, but also with immunological changes including the switch from Th2 to Th1 type response.

Full Text

The Full Text of this article is available as a PDF (467.5 KB).

Selected References

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

  1. 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]
  2. Equi A., Balfour-Lynn I. M., Bush A., Rosenthal M. Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial. Lancet. 2002 Sep 28;360(9338):978–984. doi: 10.1016/s0140-6736(02)11081-6. [DOI] [PubMed] [Google Scholar]
  3. Hand W. L., Hand D. L., King-Thompson N. L. Antibiotic inhibition of the respiratory burst response in human polymorphonuclear leukocytes. Antimicrob Agents Chemother. 1990 May;34(5):863–870. doi: 10.1128/aac.34.5.863. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Jaffé A., Bush A. Anti-inflammatory effects of macrolides in lung disease. Pediatr Pulmonol. 2001 Jun;31(6):464–473. doi: 10.1002/ppul.1076. [DOI] [PubMed] [Google Scholar]
  5. 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]
  6. Johansen H. K., Cryz S. J., Jr, Hougen H. P., Moser C., Høiby N. Vaccination promotes TH1-like inflammation and survival in chronic Pseudomonas aeruginosa pneumonia. A new prophylactic principle. Behring Inst Mitt. 1997 Feb;(98):269–273. [PubMed] [Google Scholar]
  7. Kadota J., Sakito O., Kohno S., Sawa H., Mukae H., Oda H., Kawakami K., Fukushima K., Hiratani K., Hara K. A mechanism of erythromycin treatment in patients with diffuse panbronchiolitis. Am Rev Respir Dis. 1993 Jan;147(1):153–159. doi: 10.1164/ajrccm/147.1.153. [DOI] [PubMed] [Google Scholar]
  8. Kaminskaia G. O., Zhukova N. L., Stepanian I. E. Sravnenie dvukh metodov opredeleniia i otsenki poluchennykh rezul'tatov pri issledovanii élastoliticheskoi aktivnosti mokroty. Lab Delo. 1984;(2):110–113. [PubMed] [Google Scholar]
  9. Kawasaki S., Takizawa H., Ohtoshi T., Takeuchi N., Kohyama T., Nakamura H., Kasama T., Kobayashi K., Nakahara K., Morita Y. Roxithromycin inhibits cytokine production by and neutrophil attachment to human bronchial epithelial cells in vitro. Antimicrob Agents Chemother. 1998 Jun;42(6):1499–1502. doi: 10.1128/aac.42.6.1499. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Khair O. A., Devalia J. L., Abdelaziz M. M., Sapsford R. J., Davies R. J. Effect of erythromycin on Haemophilus influenzae endotoxin-induced release of IL-6, IL-8 and sICAM-1 by cultured human bronchial epithelial cells. Eur Respir J. 1995 Sep;8(9):1451–1457. [PubMed] [Google Scholar]
  11. 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]
  12. 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]
  13. Labro M. T. Anti-inflammatory activity of macrolides: a new therapeutic potential? J Antimicrob Chemother. 1998 Mar;41 (Suppl B):37–46. doi: 10.1093/jac/41.suppl_2.37. [DOI] [PubMed] [Google Scholar]
  14. Labro M. T., el Benna J., Babin-Chevaye C. Comparison of the in-vitro effect of several macrolides on the oxidative burst of human neutrophils. J Antimicrob Chemother. 1989 Oct;24(4):561–572. doi: 10.1093/jac/24.4.561. [DOI] [PubMed] [Google Scholar]
  15. Mikasa K., Sawaki M., Kita E., Hamada K., Teramoto S., Sakamoto M., Maeda K., Konishi M., Narita N. Significant survival benefit to patients with advanced non-small-cell lung cancer from treatment with clarithromycin. Chemotherapy. 1997 Jul-Aug;43(4):288–296. doi: 10.1159/000239580. [DOI] [PubMed] [Google Scholar]
  16. Morikawa K., Oseko F., Morikawa S., Iwamoto K. Immunomodulatory effects of three macrolides, midecamycin acetate, josamycin, and clarithromycin, on human T-lymphocyte function in vitro. Antimicrob Agents Chemother. 1994 Nov;38(11):2643–2647. doi: 10.1128/aac.38.11.2643. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Morikawa K., Watabe H., Araake M., Morikawa S. Modulatory effect of antibiotics on cytokine production by human monocytes in vitro. Antimicrob Agents Chemother. 1996 Jun;40(6):1366–1370. doi: 10.1128/aac.40.6.1366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Moser C., Hougen H. P., Song Z., Rygaard J., Kharazmi A., Høiby N. Early immune response in susceptible and resistant mice strains with chronic Pseudomonas aeruginosa lung infection determines the type of T-helper cell response. APMIS. 1999 Dec;107(12):1093–1100. doi: 10.1111/j.1699-0463.1999.tb01514.x. [DOI] [PubMed] [Google Scholar]
  19. Moser C., Kjaergaard S., Pressler T., Kharazmi A., Koch C., Høiby N. The immune response to chronic Pseudomonas aeruginosa lung infection in cystic fibrosis patients is predominantly of the Th2 type. APMIS. 2000 May;108(5):329–335. doi: 10.1034/j.1600-0463.2000.d01-64.x. [DOI] [PubMed] [Google Scholar]
  20. Nelson S., Summer W. R., Terry P. B., Warr G. A., Jakab G. J. Erythromycin-induced suppression of pulmonary antibacterial defenses. A potential mechanism of superinfection in the lung. Am Rev Respir Dis. 1987 Nov;136(5):1207–1212. doi: 10.1164/ajrccm/136.5.1207. [DOI] [PubMed] [Google Scholar]
  21. Sakamoto M., Mikasa K., Majima T., Hamada K., Konishi M., Maeda K., Kita E., Narita N. Anti-cachectic effect of clarithromycin for patients with unresectable non-small cell lung cancer. Chemotherapy. 2001 Dec;47(6):444–451. doi: 10.1159/000048556. [DOI] [PubMed] [Google Scholar]
  22. Sassa K., Mizushima Y., Fujishita T., Oosaki R., Kobayashi M. Therapeutic effect of clarithromycin on a transplanted tumor in rats. Antimicrob Agents Chemother. 1999 Jan;43(1):67–72. doi: 10.1128/aac.43.1.67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Schultz M. J., Speelman P., Zaat S., van Deventer S. J., van der Poll T. Erythromycin inhibits tumor necrosis factor alpha and interleukin 6 production induced by heat-killed Streptococcus pneumoniae in whole blood. Antimicrob Agents Chemother. 1998 Jul;42(7):1605–1609. doi: 10.1128/aac.42.7.1605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Takeshita K., Yamagishi I., Harada M., Otomo S., Nakagawa T., Mizushima Y. Immunological and anti-inflammatory effects of clarithromycin: inhibition of interleukin 1 production of murine peritoneal macrophages. Drugs Exp Clin Res. 1989;15(11-12):527–533. [PubMed] [Google Scholar]
  25. Visser L., Blout E. R. The use of p-nitrophenyl N-tert-butyloxycarbonyl-L-alaninate as substrate for elastase. Biochim Biophys Acta. 1972 Apr 7;268(1):257–260. doi: 10.1016/0005-2744(72)90223-9. [DOI] [PubMed] [Google Scholar]
  26. Wales D., Woodhead M. The anti-inflammatory effects of macrolides. Thorax. 1999 Aug;54 (Suppl 2):S58–S62. doi: 10.1136/thx.54.2008.s58. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Wolter J., Seeney S., Bell S., Bowler S., Masel P., McCormack J. Effect of long term treatment with azithromycin on disease parameters in cystic fibrosis: a randomised trial. Thorax. 2002 Mar;57(3):212–216. doi: 10.1136/thorax.57.3.212. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Yanagihara K., Kadoto J., Kohno S. Diffuse panbronchiolitis--pathophysiology and treatment mechanisms. Int J Antimicrob Agents. 2001;18 (Suppl 1):S83–S87. doi: 10.1016/s0924-8579(01)00403-4. [DOI] [PubMed] [Google Scholar]

Articles from Mediators of Inflammation are provided here courtesy of Wiley

RESOURCES