Effect of Azithromycin on the Severity of Bronchial Hyperresponsiveness in Patients with Mild Asthma

Azithromycin is used in long-term, low-dose treatment of airway diseases where airway wall remodelling is present. Since it improves total score symptom and respiratory function of such patients, we hypothesise that azithromycin's additional clinical benefits are due to an inhibition of airway smooth muscle cell (SMC) proliferation.Rabbit tracheal SMCs were treated with azithromycin (10 -5 to 10 -6 M) in the presence or absence of 10% fetal bovine serum (FBS). The proliferation was estimated using the Cell Titer 961 AQ ueous One Solution Assay (Promega, Madison, WI, USA). Cell viability was assessed with Trypan blue staining and flow cytometry after 7-aminoactinomycin D (7-AAD) staining. Induction of autophagy was studied by indirect immmunofluorescence and/or Western blotting with antibodies against human smooth muscle a-actin, beclin 1, light chain 3 and caspase 3. The involvement of the phosphoinositide 3-kinase pathway was investigated with the inhibitors LY294002 and wortmannin. Incubation with azithromycin for 72 h in the presence of FBS reduced SMC proliferation and viability in a dose-dependent manner. Azithromycin treatment was accompanied by the formation of cytoplasmic vacuoles, characteristic of autophagy. All these effects were reversible after azithromycin removal and prevented by the autophagy inhibitor, 3-methyladenine, or LY294002, but not by wortmannin.In conclusion, azithromycin reduces proliferation and causes autophagy of airway SMCs.KEYWORDS: Airway smooth muscle cells, autophagy, azithromycin, proliferation M acrolide antibiotics are widely used for the treatment of airway diseases. Lowdose, long-term macrolide therapy has been reported to be very effective in patients with chronic airway diseases, such as diffuse panbronchiolitis, chronic bronchitis and bronchial asthma [1][2][3][4][5]. In many of these diseases, airway wall remodelling is present. Airway wall remodelling includes thickening of the reticular membrane, proliferation of the smooth muscle cells (SMCs) and increase in both number and size of vessels [6,7].The improvement of pulmonary function, total score symptom and quality of life with macrolides is mainly attributed to their antimicrobial and anti-inflammatory activity. However, data available from studies on airway smooth muscle show an effect of macrolides on the contractility of airway smooth muscle. Specifically, erythromycin inhibits cholinergic neuroeffector transmission in the airways [8,9] and azithromycin has a direct relaxant effect on precontracted rabbit airway smooth muscle [10].It is possible that azithromycin has an additional effect in airway SMC proliferation. As has been shown previously, erythromycin inhibits hypertrophic and metaplastic changes of goblet cells in rat nasal epithelium [11], roxithromycin inhibits proliferation of human coronary artery SMCs [12], and rapamycin and its analogue SAR943 inhibit proliferation of human epithelial and SMCs [13], while clarithromycin and azithromycin induce apoptosis of activated lymphocytes [14]. In o...

Section: Discussionmentioning

confidence: 99%

Azithromycin has an antiproliferative and autophagic effect on airway smooth muscle cells

Stamatiou

Paraskeva

Boukas

et al. 2009

“…The second study examined asthmatics taking 800 mg budesonide daily; serum-free cortisol levels showed no change from baseline levels after treatment with clarithromycin, suggesting that altered steroid metabolism was not the effect mechanism [47]. Evidence for reduced bronchial hyperresponsiveness has also been demonstrated after treatment with erythromycin, roxithromycin and azithromycin [55][56][57]. A more recent study of SIMPSON et al [45] showed improvements in quality-of-life scores and significant reductions in wheezing in patients with refractory asthma.…”

Section: Asthmamentioning

confidence: 99%

Long-term macrolide therapy in chronic inflammatory airway diseases

Crosbie¹,

Woodhead²

2009

119

In addition to direct antibacterial actions, 14-and 15-member-ring macrolides have immune modulating effects that appear to be the reason for clinical benefit in diffuse panbronchiolitis.A literature search was conducted for studies of the clinical effectiveness of macrolides in other chronic lung conditions.A number of studies were identified that showed short-term beneficial outcomes or the potential for such outcomes in cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease, asthma and post-transplant obliterative bronchiolitis. The studies were limited by small patient numbers, different outcome measures and short-term follow-up, and were not designed to assess potentially harmful effects.Further large prospective and long-term studies are required in order to identify potential benefit and harm before these agents can be recommended routinely for these conditions.

“…Values for allergen provocative concentration causing a 20% drop in FEV1 (PC20) were also improved. Similarly, EKICI et al [115] found that administration of low-dose, intermittent azithromycin (250 mg b.i.w.) to patients with mild asthma resulted in significantly increased values for PC20, although FEV1 values did not differ significantly after 8 weeks of treatment.…”

Section: Therapymentioning

confidence: 99%

Atypical pathogens and respiratory tract infections

Blasi¹

2004

107

The atypical respiratory pathogens Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila are now recognised as a significant cause of acute respiratory-tract infections, implicated in community-acquired pneumonia, acute exacerbations of chronic bronchitis, asthma, and less frequently, upper respiratory-tract infections.Chronic infection with C. pneumoniae is common among patients with chronic obstructive pulmonary disease and may also play a role in the natural history of asthma, including exacerbations. The lack of a gold standard for diagnosis of these pathogens still handicaps the current understanding of their true prevalence and role in the pathogenesis of acute and chronic respiratory infections.While molecular diagnostic techniques, such as polymerase chain reaction, offer improvements in sensitivity, specificity and rapidity over culture and serology, the need remains for a consistent and reproducible diagnostic technique, available to all microbiology laboratories.Current treatment guidelines for community-acquired pneumonia recognise the importance of atypical respiratory pathogens in its aetiology, for which macrolides are considered suitable first-line agents. The value of atypical coverage in antibiotic therapy for acute exacerbations of chronic bronchitis and exacerbations of asthma is less clear, while there is no evidence to suggest that atypical pathogens should be covered in antibiotic treatment of upper respiratory-tract infections. The term "atypical pathogen" most commonly refers to Chlamydia pneumoniae, Mycoplasma pneumoniae and Legionella pneumophila. Once believed to be of little clinical significance, a wealth of data accumulated over the past decade suggests that these are important respiratory pathogens in a wide range of respiratory-tract infections (RTIs) and are capable of causing severe, as well as mild-to-moderate, illness.Although the role of atypical pathogens [1], and of C. pneumoniae in particular [2], has been reviewed previously, there has been little focus on appropriate coverage of these pathogens in treatment decisions for patients with RTIs. In addressing this issue, this review examines the role of atypical pathogens in the aetiology of upper and lower RTIs, in both adults and children, and discusses the value of appropriate coverage of these pathogens in empirical antibiotic prescribing.