18th International Congress of Pediatric Pulmonology Tokyo Chiba, June 27 - 30, 2019.

Abstract

Pediatric PulmonologyVolume 54, Issue S1 p. S6-S6 ABSTRACTSFree Access Keynote Lecture First published: 27 June 2019 https://doi.org/10.1002/ppul.24369AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat 1 Macrolides – From Diffuse Pan-Bronchiolitis to CF and Beyond Bruce K. Rubin MEngr, MD, MBA, FRCPC Virginia Commonwealth University Department of Pediatrics and The Children’s Hospital of Richmond at VCU, Richmond, VA Email: bruce.rubin@vcuhealth.org The term “macrolide” describes drugs with a macrocyclic lactone ring of twelve or more elements. The nonantimicrobial properties of macrolides were suspected as far back as the 1960s, however their dramatic clinical effectiveness in treating diffuse panbronchiolitis has served to extend their use to a number of chronic inflammatory diseases including cystic fibrosis, non-CF bronchiectasis, chronic obstructive pulmonary disease, and chronic rhinosinusitis. Macrolide antibiotics administered in subantimicrobial doses improve pulmonary function and decrease exacerbation frequency for persons with bronchiectasis or cystic fibrosis. Data also suggest a beneficial effect of macrolide antibiotics in the treatment of steroid-dependent (neutrophil dominant) asthma and chronic obstructive pulmonary disease.1 The immunomodulatory effects of macrolides in patients with chronic inflammatory airway disease are independent of their antimicrobial properties and have been demonstrated in 14- and 15- (but not 16-) member macrolides that are devoid of antimicrobial activity. Immunomodulation, which differs from immunosuppression or anti-inflammation, is a nonlinear resetting of the immune response by modifying or regulating one or more functions of the immune system. We use the term immunomodulation to describe the downregulation of a hyperimmunity or hyperinflammation without impairing the normal immune or inflammatory response to defend against infection. Macrolides initially decrease, then increase, and have finally a sustained suppression of cytokine secretions from normal human bronchial epithelial cells through inhibition and activation of extracellular signal-regulated kinases (ERKs) and then reversibly retard cell proliferation probably through ERK. Macrolides are not anti-inflammatory but are true immunomodulators.2, 3 Consistent with this, macrolide antibiotics reduce mucin production as well as neutrophil migration by interfering with ERK signal transduction. Macrolides accumulate within cells, suggesting that they may associate with receptors or carriers responsible for the regulation of immune cell activities.4 Chronic macrolide use at low dosage as an immunomodulator drug will inevitably induce antimicrobial resistance. There are two principal forms of acquired macrolide resistance. Low level resistance or Mef, by far the most common, involves the activation of efflux pumps to drive the antibiotic out of the target cell. This can be overcome by higher doses of the drug and is reversible if antibiotic pressure is reversed. High level, or Erm, resistance involves an irreversible modification of the bacterial ribosome target. This is heritable and cannot be overcome by a higher concentration of drug.5 Other ERK inhibitors that can be administered as an aerosol are under development as novel therapy for neutrophil dominant airway disease.6 REFERENCES 1Rubin BK, Tamaoki J. Antibiotics as Anti-inflammatory and Immunomodulatory Agents. Basel. Birkhäuser Verlag AG; November 2004. 2Shinkai M, Foster GH, Rubin BK. Macrolide antibiotics modulate ERK phosphorylation and IL-8 and GM-CSF production by human bronchial epithelial cells. Am J Physiol Lung Cell Molec Physiol. 2006; 290: L75- L85. 3Kanoh S, Rubin BK. Mechanisms of action and clinical application of macrolides as immunomodulatory medications. Clinical Microbiol Rev. 2010; 23: 590- 615. 4Tanabe T, Kanoh S, Tsushima K, Yamazaki Y, Kubo K, Rubin BK. Clarithromycin inhibits interleukin-13-induced goblet cell hyperplasia in human airway cells. Am J Respir Cell Mol Biol. 2011; 45: 1075- 1083. 5Shinkai M, Rubin BK. Macrolides and airway inflammation in children. Pediatr Resp Rev. 2005; 6: 227- 235. 6Kanoh S, Tanabe T, Rubin BK. Dapsone inhibits IL-8 secretion from human bronchial epithelial cells stimulated with LPS and resolves airway inflammation in the ferret. Chest. 2011; 140: 980- 990. Volume54, IssueS1Supplement: 18th International Congress of Pediatric Pulmonology Tokyo Chiba, June 27 – 30, 2019June 2019Pages S6-S6 ReferencesRelatedInformation