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We also showed defects in phagocytosis of nontypeable Haemophilus influenzae (NTHi), a common colonizer of the lower airway in these diseases. These defects could be substantially overcome with low-dose azithromycin; however, chronic use may induce bacterial resistance. The aim of the present study was therefore to investigate two novel macrolides\u20142\u2032-desoxy-9-(S)-erythromycylamine (GS-459755) and azithromycin-based 2\u2032-desoxy molecule (GS-560660)\u2014with significantly diminished antibiotic activity against Staphylococcus aureus, Streptococcus pneumonia, Moraxella catarrhalis, and H. influenzae. We tested their effects on efferocytosis, phagocytosis of NTHi, cell viability, receptors involved in recognition of apoptotic cells and\/or NTHi (flow cytometry), secreted and cleaved intracellular IL-1\u03b2 (cytometric bead array, immunofluorescence\/confocal microscopy), and nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) using primary alveolar macrophages and THP-1 macrophages \u00b1 10% cigarette smoke extract. Dose-response experiments showed optimal prophagocytic effects of GS-459755 and GS-560660 at concentrations of 0.5\u20131 \u00b5g\/ml compared with our findings with azithromycin. Both macrolides significantly improved phagocytosis of apoptotic cells and NTHi (e.g., increases in efferocytosis and phagocytosis of NTHi: GS-459755, 23 and 22.5%, P = 0.043; GS-560660, 23.5 and 22%, P = 0.043, respectively). Macrophage viability remained &gt;85% following 24 h exposure to either macrolide at concentrations up to 20 \u00b5g\/ml. Secreted and intracellular-cleaved IL-1\u03b2 was decreased with both macrolides with no significant changes in recognition molecules c-mer proto-oncogene tyrosine kinase; scavenger receptor class A, member 1; Toll-like receptor 2\/4; or CD36. Particulate cytoplasmic immunofluorescence of NLRP3 inflammasome was also reduced significantly. We conclude that GS-459755 and GS-560660 may be useful for reducing airway inflammation in chronic lung diseases without inducing bacterial resistance. <\/jats:p>","DOI":"10.1152\/ajplung.00518.2016","type":"journal-article","created":{"date-parts":[[2017,3,3]],"date-time":"2017-03-03T20:25:28Z","timestamp":1488572728000},"page":"L678-L687","source":"Crossref","is-referenced-by-count":55,"title":["Nonantibiotic macrolides restore airway macrophage phagocytic function with potential anti-inflammatory effects in chronic lung diseases"],"prefix":"10.1152","volume":"312","author":[{"given":"Sandra","family":"Hodge","sequence":"first","affiliation":[{"name":"Lung Research Unit, Hanson Institute, and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia;"},{"name":"Department of Medicine, University of Adelaide, Adelaide, Australia; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai B.","family":"Tran","sequence":"additional","affiliation":[{"name":"Lung Research Unit, Hanson Institute, and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rhys","family":"Hamon","sequence":"additional","affiliation":[{"name":"Lung Research Unit, Hanson Institute, and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eugene","family":"Roscioli","sequence":"additional","affiliation":[{"name":"Lung Research Unit, Hanson Institute, and Department of Thoracic Medicine, Royal Adelaide Hospital, Adelaide, Australia;"},{"name":"Department of Medicine, University of Adelaide, Adelaide, Australia; 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