PDF icon Download PDF
Semin Respir Crit Care Med 2003; 24(6): 737-748
DOI: 10.1055/s-2004-815669
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Macrolides as Biological Response Modifiers in Cystic Fibrosis and Bronchiectasis

Andrew Bush1,2 , Bruce K. Rubin3,4
  • 1Department of Pediatric Respirology, Imperial School of Medicine at National Heart and Lung Institute
  • 2Royal Brompton Hospital, London, United Kingdom
  • 3Department of Pediatrics, Wake Forest University Health Sciences, Winston-Salem, North Carolina
  • 4Department Biomedical Engineering, Physiology and Pharmacology, Wake Forest University Health Sciences, Winston-Salem, North Carolina
Further Information

Publication History

Publication Date:
15 January 2004 (online)

   Permissions and Reprints
Preview

ABSTRACT

For 50 years, macrolide antibiotics have been used to treat community acquired pneumonia and atypical infections such as Chlamydia pneumonia and Mycoplasma. In the late 1960s it was noted that when the 14-member ring macrolide antibiotic troleandomycin was given to asthma patients who required large doses of systemic corticosteroids, they could often reduce their steroid dose or even stop steroids completely without exacerbation of their asthma. Because of this experience, Prof. S. Kodoh and colleagues first used erythromycin as an immunomodulatory agent to treat diffuse panbronchiolitis (DPB). DPB is a cystic fibrosis (CF)-like condition seen predominantly in young, nonsmoking adults in Japan and Korea. The introduction of erythromycin profoundly improved survival, and in many of these very ill patients the illness disappeared. Since then, research has focused attention on many nonantibacterial, disease modifying effects of this class of compounds. These include downregulation of proinflammatory cytokines via an effect on nuclear transcription factors, reduction in adhesion molecule expression, suppression of inducible nitric oxide synthase (iNOS), reduced neutrophil chemotaxis and degranulation, inhibition of neutrophil elastase, cytoprotection against bioactive phospholipids, improvement in the rheological properties of mucus, reduction in bronchial hyperreactivity, and, perhaps, modulation of neutrophil death by apoptosis pathways, and in the end, airway remodeling. Additionally, they have unconventional effects on microorganisms, including inhibiting Pseudomonas aeruginosa twitching motility and thus biofilm formation. There are small case series and three large randomized controlled trials that have established unequivocal evidence of benefit in CF. There is less evidence for an immunomodulatory effect in bronchiectasis. Future work is likely to focus on the development of macrolides with disease-specific modes of action.

KEYWORDS

Cystic fibrosis - bronchiectasis - macrolide - cytokine - adhesion molecule - diffuse panbronchiolitis - neutrophils

REFERENCES