Chest
Volume 125, Issue 2, Supplement, February 2004, Pages 41S-51S
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The Effects of Macrolides on Inflammatory Cells

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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.

Section snippets

Neutrophil Functions

Neutrophils act selectively in their proinflammatory role by simultaneously integrating multiple signals derived from high-affinity integrins, from inflammatory cytokines, and from chemoattractants produced by bacteria and epithelial cells of inflamed tissues. Historically, neutrophils have been considered to be lacking in transcriptional activity. However, molecular evidence now indicates that the human neutrophil is a source of various proinflammatory cytokines, chemokines, and growth

Effects of Macrolides on Neutrophil Accumulation

There is some disagreement as to the effects of macrolide antibiotics on neutrophil migration. To date, the inhibitory effects in vitro11 and in vivo12 have been described, while others have reported either no effect in vitro13 or stimulatory effects in vitro and in vivo.14 The reason for this controversy is unknown but might be due to differences in species and/or experimental conditions. Kawasaki et al15 conducted an in vitro study of the potential effects of roxithromycin on neutrophil

The Effect of Macrolides on Molecular Targets

As a primary anti-inflammatory activity, the macrolides appear to target nuclear transcriptional regulation. The stimulation of cells with various cytokines (eg, IL-8 and TNF-α) induces and activates a number of nuclear DNA-binding proteins, which in turn trigger the transcriptional process to initiate and amplify the inflammatory response.17

Nuclear factor-κB (NF-κB) is a protein that is essential for the transcription of genes that encode a number of proinflammatory molecules that participate

The Effects of Macrolides on Immune Complex-Induced Lung Injury

The gaseous molecule nitric oxide (NO) is a second messenger that is produced by NO synthase (NOS), which exists in both constitutive NOS and iNOS isoforms. NOS catalyzes the conversion of L-arginine to L-citrulline and NO. NO participates in a number of normal physiologic processes and also acts as an inflammatory mediator, thereby playing a role in the pathogenesis of lung inflammation and injury.21 Several cell types, including neutrophils, airway epithelial cells, and pulmonary macrophages,

The Effects of Macrolides on Airway Goblet Cell Secretion

LPS endotoxin comprises a major portion of the cell walls of Gram-negative bacteria and interacts with a variety of cell types, including neutrophils, basophils, and monocytes. Studies have demonstrated that LPS increases microvascular permeability, neutrophil chemotaxis, accumulation into the airway wall and, hence, neutrophilic airway inflammation.

To determine the effects of LPS on airway goblet cell secretion, Tamaoki and colleagues16 pretreated pathogen-free guinea pigs with single daily

The Effects of Macrolides on Mucin Production

Mucins are macromolecular glycoproteins that impart viscoelastic properties to mucus. Airway mucus protects the epithelial surface from injury and facilitates the removal of bacterial, cellular, and particulate debris from the lung. Goblet cells and submucosal glands secrete mucus, and ciliated epithelial cells clear these secretions by a mucociliary transport system, which propels mucus through the airways toward the nose and throat. Mucins also play a principal role in the pathogenesis of

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-κB activation that leads to IL-8 production and enhanced neutrophil accumulation. Additionally, in vitro studies have suggested that macrolides inhibit the

CME Questions

The American College of Chest Physicians designates this continuing medical education activity for 1 credit hour in category 1 of the Physician's Recognition Award of the American Medical Association. To obtain credit, please complete the question form at www.chestnet.org. Credit can be obtained ONLY through our online process.

  • 1.

    Which of the following drugs does not inhibit the release of NO?

    • A.

      Clarithromycin

    • B.

      Roxithromycin

    • C.

      Erythromycin

    • D.

      Amoxicillin

    • E.

      Josamycin

  • 2.

    Proposed mechanisms of action of

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  • Learning objectives:

    • 1.

      To recognize the proposed mechanisms of action of macrolides for the treatment of chronic diseases of the airways.

    • 2.

      To understand the mechanisms by which macrolides affect the accumulation of neutrophils in chronic diseases of the airways.

    • 3.

      To understand the effects of macrolides on NO-induced lung inflammation and injury.

    • 4.

      To understand the effects of macrolides on airway goblet cell secretion.

    • 5.

      To understand the effects of macrolides on mucin production.

    Neither Dr. Tamaoki nor the department(s) with which he is affiliated have received something of value (ie, any item, payment, or service valued in excess of $750.00) from a commercial or other party related directly or indirectly to the subject of this submission.

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