macrolides and inflammatory pathways

Written by on November 28, 2005 in macrolides with 0 Comments

The Effects of Macrolides on Inflammatory Cells

Chest, 2004;125:41S-51S.

Jun Tamaoki, MD, FCCP

First Department of Medicine, Tokyo Women’s Medical University School of Medicine Tokyo, Japan.

Abstract: Bronchial epithelial damage and mucus hypersecretion are characteristic features of chronic airway inflammation that can impair mucociliary clearance and can cause recurrent or persistent respiratory infection. In response to chemoattractants produced by damaged or inflamed tissue, neutrophils move through sequential steps of recruitment, migration, accumulation, and adhesion to endothelial and bronchial epithelial cells. Neutrophils engage in bacteriocidal activity by phagocytosis, release of lysosomal enzymes, and generation of reactive oxygen species, and they synthesize and release proinflammatory cytokines. Data confirm that many macrolide antibiotics have nonbactericidal properties that include inhibiting inflammatory cell chemotaxis, cytokine synthesis, adhesion molecule expression, and reactive oxygen species production. Macrolides also can decrease airway mucus hypersecretion in patients with diffuse panbronchiolitis, chronic sinusitis, and chronic bronchitis. Macrolides accumulate in neutrophils and macrophages at significantly higher concentrations than in extracellular fluid. This article discusses the action of macrolides on neutrophil accumulation, immune complex-mediated production of nitric oxide, mucin production, and the expanded therapeutic role of macrolides as biological response modifiers.

Key Words: airway epithelium • diffuse panbronchiolitis • immune complex deposition • macrolides • neutrophils • nitric oxide

Conclusion: Investigations into the biological response-modifying properties of the macrolides have uncovered a variety of salutary effects and plausible mechanisms of action by which the extrabactericidal properties of macrolides impact the immune system. Macrolides appear to modulate inflammatory activity in airway epithelial cells by inhibiting NF-B activation that leads to IL-8 production and enhanced neutrophil accumulation. Additionally, in vitro studies have suggested that macrolides inhibit the expression of ICAM, thereby also modulating the recruitment of neutrophils to inflamed sites. The extraribosomal effects of macrolides reduce the number of neutrophils in the BAL fluid from patients with neutrophilic, inflammatory airway diseases. In such diseases as DPB, cystic fibrosis, acute exacerbation of chronic bronchitis, and COPD, macrolides also may attenuate mucus hypersecretion by goblet cells as an indirect consequence of inhibiting neutrophil migration, activation, and accumulation.

The function of macrolide antibiotics as biological response modifiers must be explained in the context of their integrated effects on the activation of nuclear transcription factors, the gene expression of inflammatory mediators, and specific cellular targets. A thorough understanding of the biological properties of macrolides in the host either to disrupt or to redirect signaling pathways that lead to prolonged inflammation and airway hypersecretion should establish a firm foundation on which to construct novel therapies that effectively prevent or ameliorate both the symptoms and the long-term morbidity of chronic respiratory illnesses.

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About the Author: David Pascoe started the Rosacea Support Group in October 1998. .

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