Novel Effects of Azithromycin on Tight Junction Proteins in Human Airway Epithelia

Abstract

The macrolide antibiotic azithromycin improves lung function and prognosis among patients with cystic fibrosis or diffuse panbronchiolitis, independently of bacterial eradication. Anti-inflammatory effects have been implicated, but data from in vivo studies are scarce, and the link between abnormal electrolyte content in airway surface liquid and bronchial infections remains uncertain.In the present study, we treated human airway epithelia on filter supports with azithromycin and monitored transepithelial electrical resistance. We found that azithromycin increased transepithelial electrical resistance of airway epithelia in a dose-dependent manner. Immunocytochemistry and Western blotting showed that addition of azithromycin changed the locations of proteins in cell cultures and induced processing of the tight junction proteins claudin-1 and claudin-4, occludin, and junctional adhesion molecule-A. These effects were reversible, and no effect was seen when cells were treated with penicillin or erythromycin. The data indicate that azithromycin increases the transepithelial electrical resistance of human airway epithelia by changing the processing of tight junction proteins. The results are novel and may help explain the beneficial effects of azithromycin in patients with cystic fibrosis, diffuse panbronchiolitis, and community-acquired pneumonia.

Acute regulation of tight junction ion selectivity in human airway epithelia

“…Thus, as with many other epithelia (6,8), airway epithelia express multiple claudins. Our data agree with earlier studies reporting that primary cultures of airway epithelia express claudins 1, 3, 4, and 7, but not claudins 2, 5, 6, 9, 10, 11 or 15 (25,26). One difference is that we detected claudin-10 variant 2 (but not variant 1) and claudin 16, whereas they were not detected in another study (25).…”

“…In contrast to our data, azithromycin and shear stress decreased G p . The former occurred over the course of days in association with altered processing of tight junction proteins (26), and the latter required serial activation of the transient receptor potential vanilloid-4 channel and L-type voltage-gated calcium channel (38). Studies in other epithelia have also revealed regulation of tight junction permeability.…”

Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications

“…Oral administration of roxithromycin significantly ameliorated PAF-induced ciliary dysfunction and the increase in epithelial permeability. Azithromycin, but not penicillin or erythromycin, increased the transepithelial electrical resistance (barrier) of human airway epithelial cells cultured on filter supports (16). In this model, azithromycin induced processing of the tight junction proteins claudin-1, claudin-4, occludin, and junctional adhesion molecule A.…”

Relationship between Azithromycin Susceptibility and Administration Efficacy for Nontypeable Haemophilus influenzae Respiratory Infection

“…In addition to their direct antibacterial effect, macrolides are immunomodulators, presenting anti-inflammatory activities on cells of the innate and adaptive immunity and on structural cells (16)(17)(18). On airway epithelia, macrolides positively regulate tight junctions (19) and suppress the activation of NF-B, Sp1, and AP-1, leading to a reduction of proinflammatory cytokines (20)(21)(22)(23)(24)(25). On phagocytes, besides decreasing the secretion of proinflammatory cytokines, macrolides stimulate monocyte differentiation into alveolar macrophages, improve phagocytic function, and favor expression of the phagocytic mannose receptor in COPD patients (26)(27)(28)(29)(30)(31).…”