Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection

Renna, Maurizio; Schaffner, Catherine; Brown, Karen; Shang, Shaobin; Tamayo, Marcela Henao; Hegyi, Krisztina; Grimsey, Neil; Cusens, David; Coulter, Sarah; Cooper, Jason; Bowden, A.; Newton, Sandra M.; Kampmann, Beate; Helm, Jenny; Jones, Andrew M.; Haworth, Charles; Basaraba, Randall J.; DeGroote, Mary Ann; Ordway, Diane; Rubinsztein, David C.; Floto, R. Andres

doi:10.1172/jci46095

Cited by 289 publications

(282 citation statements)

References 32 publications

(35 reference statements)

Supporting

Mentioning

261

Contrasting

Unclassified

Order By: Relevance

“…Recent studies suggest a relationship between MABSC infection and long-term low-dose azithromycin treatment [4,26]. However, we did not find a significant positive association between the presence of MABSC in sputum and the use of the other ''new'' therapeutic approaches to CF such as inhaled therapies or long-term azithromycin.…”

Section: Discussioncontrasting

confidence: 89%

“…Thus, low-dose azithromycin maintenance treatment cannot prevent colonisation and further infection with MABSC in most cases. In addition, the antiinflammatory effects of this treatment may impair the immune response to mycobacteria, as suggested in a recent study [26].…”

mentioning

confidence: 76%

“…As MABSC isolates are usually resistant to azithromycin, MABSC may be selected by long-term azithromycin treatment in CF patients. In addition, a recent study also suggested that azithromycin may increase susceptibility to mycobacterial disease by inhibiting the autophagy-dependent killing of mycobacteria [26]. Prior treatment with azithromycin was shown to result in significant alkalinisation of the mycobacterial phagosome, to pH levels inhibiting most lysosomal proteases in RAW 264.7 cells, and to prevent basal intracellular killing and the interferon (IFN)-c-and tumour necrosis factor (TNF)-dependent killing of M. abscessus in primary human macrophages.…”

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Inhaled therapies, azithromycin andMycobacterium abscessusin cystic fibrosis patients

Catherinot¹,

Roux²,

Vibet³

et al. 2012

Eur Respir J

View full text Add to dashboard Cite

Cystic fibrosis (CF) patients are at particularly high risk of developing lung disease caused by Mycobacterium abscessus complex (MABSC). Over the last 10 years, changes in CF treatment, with increasing use of inhaled therapies and low-dose azithromycin, have been accompanied by an increase in the prevalence of MABSC infections in CF patients. There is therefore some concern about the role of new CF treatments in the emergence of MABSC infections.We addressed this issue by means of a case-control study including 30 MABSC-positive cases and 60 nontuberculous mycobacteria-negative CF controls matched for age, sex and centre. We also compared practices at the CF centres with the highest prevalence of MABSC with those at the other centres.No positive association was found between MABSC lung disease and the use of inhaled therapies or low-dose azithromycin in the 4 years preceding MABSC isolation. These treatments were not significantly more frequently used at the CF centres with the highest MABSC prevalence rates.In conclusion, there is no evidence for a link between M. abscessus complex lung disease and inhaled therapies or low-dose azithromycin in patients with CF.

show abstract

Section: Discussioncontrasting

confidence: 89%

mentioning

confidence: 76%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Inhaled therapies, azithromycin andMycobacterium abscessusin cystic fibrosis patients

Catherinot¹,

Roux²,

Vibet³

et al. 2012

Eur Respir J

View full text Add to dashboard Cite

show abstract

“…Azithromycin, a potent macrolide antibiotic used in patients with CF is associated with increased infection with non-tuberculous mycobacteria. Interestingly, azithromycin has been shown to block autophagosome clearance by preventing lysosomal acidification, impairing autophagic and phagosomal degradation in primary human macrophages thereby inhibiting the intracellular killing of mycobacteria within macrophages in vivo (139). These studies highlight the role of maintaining regulated selective autophagy activity in patients with CF.…”

Section: Autophagy In Cystic Fibrosismentioning

confidence: 98%

Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease

Nakahira

Cloonan

Mizumura

et al. 2014

Antioxidants & Redox Signaling

View full text Add to dashboard Cite

Significance: Autophagy is a fundamental cellular process that functions in the turnover of subcellular organelles and protein. Activation of autophagy may represent a cellular defense against oxidative stress, or related conditions that cause accumulation of damaged proteins or organelles. Selective forms of autophagy can maintain organelle populations or remove aggregated proteins. Autophagy can increase survival during nutrient deficiency and play a multifunctional role in host defense, by promoting pathogen clearance and modulating innate and adaptive immune responses. Recent Advances: Autophagy has been described as an inducible response to oxidative stress. Once believed to represent a random process, recent studies have defined selective mechanisms for cargo assimilation into autophagosomes. Such mechanisms may provide for protein aggregate detoxification and mitochondrial homeostasis during oxidative stress. Although long studied as a cellular phenomenon, recent advances implicate autophagy as a component of human diseases. Altered autophagy phenotypes have been observed in various human diseases, including lung diseases such as chronic obstructive lung disease, cystic fibrosis, pulmonary hypertension, and idiopathic pulmonary fibrosis. Critical Issues: Although autophagy can represent a pro-survival process, in particular, during nutrient starvation, its role in disease pathogenesis may be multifunctional and complex. The relationship of autophagy to programmed cell death pathways is incompletely defined and varies with model system. Future Directions: Activation or inhibition of autophagy may be used to alter the progression of human diseases. Further resolution of the mechanisms by which autophagy impacts the initiation and progression of diseases may lead to the development of therapeutics specifically targeting this pathway. Antioxid. Redox Signal. 20,

show abstract

“…RENNA et al [122] demonstrated that azithromycin paradoxically inhibits intracellular killing of mycobacteria by blocking autophagy, a critical cell homeostatic process that protects against infectious, autoimmune and inflammatory diseases.…”

Section: Risks Of Long-term Macrolide Treatmentmentioning

confidence: 99%

Long-term macrolide treatment for chronic respiratory disease

2012

View full text Add to dashboard Cite

Long-term macrolide treatment was first shown to alter the natural history of diffuse panbronchiolitis (DPB) in the late 1980s. Since then, macrolides have been demonstrated to exert antiinflammatory and immunomodulatory activity in addition to being antimicrobial. Indeed, their spectrum of action extends to the regulation of leukocyte function and production of inflammatory mediators, control of mucus hypersecretion, resolution of inflammation and modulation of host defence mechanisms. As such, the potential benefit of macrolide antibiotics has been evaluated in a variety of chronic respiratory diseases. The best studied condition is cystic fibrosis, of which there have been six randomised controlled trials showing evidence of benefit. However, most of the studies were limited by small numbers of patients and short follow-up. More recently, landmark studies have demonstrated the efficacy of azithromycin in reducing the risk of acute exacerbations in patients with chronic obstructive pulmonary disease, but the optimal duration and dosing of macrolide treatment remain uncertain.With the exception of patients with DPB and cystic fibrosis, until clear evidence of efficacy is available, the long-term use of macrolides should be limited to highly selected patients after careful evaluation of benefit and harm, or in the context of randomised controlled clinical trials. @ERSpublications Several studies evaluating macrolide antibiotics for the treatment of chronic respiratory diseases are underway

show abstract

Azithromycin blocks autophagy and may predispose cystic fibrosis patients to mycobacterial infection

Cited by 289 publications

References 32 publications

Inhaled therapies, azithromycin andMycobacterium abscessusin cystic fibrosis patients

Inhaled therapies, azithromycin andMycobacterium abscessusin cystic fibrosis patients

Autophagy: A Crucial Moderator of Redox Balance, Inflammation, and Apoptosis in Lung Disease

Long-term macrolide treatment for chronic respiratory disease

Contact Info

Product

Resources

About