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A Method for Generating Pulmonary Neutrophilia Using Aerosolized Lipopolysaccharide
Published on: December 15, 2014
Azithromycin analogue CSY0073 attenuates lung inflammation induced by LPS challenge
V Balloy1, A Deveaux, D Lebeaux
1INSERM, UMR_S 938, CDR Saint-Antoine, Paris, France; Sorbonne Universités, UPMC Univ Paris 06, UMR_S 938, CDR Saint-Antoine, Paris, France; Inserm U874, Paris, France; Unité de défense Innée et Inflammation, Institut Pasteur, Paris, France.
Background And Purpose:
Azithromycin is a macrolide antibiotic with anti-inflammatory and immunomodulating effects. Long-term azithromycin therapy in patients with chronic lung diseases such as cystic fibrosis has been associated with increased antimicrobial resistance, emergence of hypermutable strains, ototoxicity and cardiac toxicity. The aim of this study was to assess the anti-inflammatory effects of the non-antibiotic azithromycin derivative CSY0073.
Experimental Approach:
We compared the effects of CSY0073 with those of azithromycin in experiments on bacterial cultures, Pseudomonas aeruginosa biofilm, lung cells and mice challenged intranasally with P. aeruginosa LPS.
Key Results:
In contrast to azithromycin, CSY0073 did not inhibit the growth of P. aeruginosa, Staphylococcus aureus or Haemophilus influenzae and had no effect on an established P. aeruginosa biofilm. Bronchoalveolar lavage (BAL) fluids and lung homogenates collected after the LPS challenge in mice showed that CSY0073 and azithromycin (200 mg·kg(-1), i.p.) decreased neutrophil counts at 24 h and TNF-α, CXCL1 and CXCL2 levels in the BAL fluid after 3 h and IL-6, CXCL2 and IL-1β levels in the lung after 3 h compared with the vehicle. However, only azithromycin reduced IL-1β levels in the lung 24 h post LPS challenge. CSY0073 and azithromycin similarly diminished the production of pro-inflammatory cytokines by macrophages, but not lung epithelial cells, exposed to P. aeruginosa LPS.
Conclusions And Implications:
Unlike azithromycin, CSY0073 had no antibacterial effects but it did have a similar anti-inflammatory profile to that of azithromycin. Hence, CSY0073 may have potential as a long-term treatment for patients with chronic lung diseases.
Insights
A novel azithromycin derivative, CSY0073, demonstrates anti-inflammatory effects without antibacterial activity. This derivative may offer a safer long-term treatment option for chronic lung diseases, avoiding antibiotic resistance issues.
Area of Science:
- Pharmacology
- Immunology
- Pulmonology
Background:
- Azithromycin, a macrolide antibiotic, possesses anti-inflammatory properties beneficial for chronic lung diseases.
- Long-term azithromycin use is linked to adverse effects including antimicrobial resistance and toxicity.
Purpose of the Study:
- To evaluate the anti-inflammatory potential of CSY0073, a non-antibiotic derivative of azithromycin.
- To compare the effects of CSY0073 and azithromycin on inflammation and bacterial growth.
Main Methods:
- Comparative analysis of CSY0073 and azithromycin effects on bacterial cultures and Pseudomonas aeruginosa biofilms.
- In vivo studies using mice models challenged with P. aeruginosa lipopolysaccharide (LPS).
- Assessment of inflammatory markers in bronchoalveolar lavage fluid and lung homogenates.
Main Results:
- CSY0073 exhibited no antibacterial activity against tested pathogens or biofilms, unlike azithromycin.
- Both CSY0073 and azithromycin reduced neutrophil counts and pro-inflammatory cytokines (TNF-α, CXCL1, CXCL2, IL-6, IL-1β) in mouse lung models post-LPS challenge.
- CSY0073 and azithromycin similarly suppressed LPS-induced pro-inflammatory cytokine production in macrophages.
Conclusions:
- CSY0073 possesses significant anti-inflammatory effects comparable to azithromycin.
- The absence of antibacterial activity makes CSY0073 a promising candidate for long-term management of chronic lung conditions.
- CSY0073 may provide therapeutic benefits without the risks associated with antibiotic resistance and toxicity.
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