Abstract:
Introduction:COPD is an inflammatory airway pathology associated with recurrent infection by nontypeable Haemophilus influenzae (NTHi) that is not effectively managed by macrolide antibiotic therapy. We hypothesised that NTHi is able to reside intracellularly within COPD-derived airway epithelial cells (AEC), and that the factors contained in cigarette smoke when coupled with exposure to erythromycin or azithromycin arrest autophagy, the principle mechanism responsible for clearing intracellular bacteria (called "xenophagy"). Methods:Cultures of bronchial airway epithelial cells derived from control and COPD participants were differentiated at an air-liquid interface and exposed to macrolide antibiotics, 10% cigarette smoke-extract (CSE) and NTHi. Markers of autophagic flux and intracellular NTHi were assessed using Western blot analysis and transmission electron microscopy. Results:AEC treated with macrolide antibiotics or 10% CSE exhibited a block in autophagic flux as evidenced by a concomitant increase in LC3-II and Sequestosome abundance (vs control; both P < 0.01). While control AEC showed no clear evidence of intracellular NTHi, COPD-derived cultures exhibited abundant NTHi within the cytoplasm. Further, intracellular NTHi that were encapsulated within vesicles propagated from the apical epithelial layer to the basal cell layer. Discussion:Taken together, our findings indicate that COPD, cigarette smoke and macrolide antibiotics potentiate the susceptibility to persistent intracellular NTHi. A major mechanism for this is arresting normal autophagic flux in airway epithelial cells. Hence, structural modifications that mitigate this off-target effect of macrolides have significant potential to clear intracellular NTHi and thereby reduce the influence of this pathogen in the airways afflicted by COPD.
journal_name
Int J Chron Obstruct Pulmon Disauthors
Poh WP,Kicic A,Lester SE,Nguyen PT,Bakaletz LO,Reynolds PN,Hodge S,Roscioli Edoi
10.2147/COPD.S245819subject
Has Abstractpub_date
2020-06-04 00:00:00pages
1253-1260eissn
1176-9106issn
1178-2005pii
245819journal_volume
15pub_type
杂志文章abstract:INTRODUCTION:While cross-national studies have documented rates of chronic obstructive pulmonary disease (COPD) misdiagnosis among patients in primary care, US studies are scarce. Studies investigating diagnosis among uninsured patients are lacking. OBJECTIVE:The purpose of this study is to identify patients who are o...
journal_title:International journal of chronic obstructive pulmonary disease
pub_type: 杂志文章
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journal_title:International journal of chronic obstructive pulmonary disease
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journal_title:International journal of chronic obstructive pulmonary disease
pub_type: 杂志文章,多中心研究,随机对照试验
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journal_title:International journal of chronic obstructive pulmonary disease
pub_type: 杂志文章,随机对照试验
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pub_type: 杂志文章,多中心研究
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pub_type: 杂志文章,随机对照试验
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pub_type: 已发布勘误
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journal_title:International journal of chronic obstructive pulmonary disease
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