Return to search

EFFECT OF AZITHROMYCIN ON MACROPHAGE PHENOTYPE DURING PULMONARY INFECTIONS AND CYSTIC FIBROSIS

Azithromycin improves clinical outcomes in patients with cystic fibrosis (CF), specifically in patients infected with Pseudomonas aeruginosa. Azithromycin shifts macrophage programming away from a pro-inflammatory classical (M1) phenotype, and towards an anti-inflammatory alternative (M2) phenotype; however, little is known about this mechanism, nor of its impact upon immune response to pulmonary infection. We set out to determine the mechanism by which azithromycin is able to alter macrophage phenotype, and assess the effect of azithromycin induced macrophage polarization on inflammation during pulmonary infections.
Utilizing macrophage cell culture, we found that azithromycin increased IKKβ, a signaling molecule in the NFκB pathway, which likely is altering macrophage programming. Using a Pseudomonas infection model in mice that lack physiologic alternative macrophage activation, we showed that azithromycin’s ability to alter macrophage function and decrease lung damage was independent of interleukin control of macrophage programming. Azithromycin increased fibrotic protein production both in vivo and in vitro, but blunted immune-driven fibrotic damage. We extended our study to patients with CF, describing gene expression in macrophages isolated from sputum samples. We found markers consistent with a shift toward M2 polarization in these patients. These data suggest potential mechanisms by which azithromycin benefits patients with CF.

Identiferoai:union.ndltd.org:uky.edu/oai:uknowledge.uky.edu:gradschool_diss-1836
Date01 January 2011
CreatorsCory, Theodore James
PublisherUKnowledge
Source SetsUniversity of Kentucky
Detected LanguageEnglish
Typetext
Formatapplication/pdf
SourceUniversity of Kentucky Doctoral Dissertations

Page generated in 0.0102 seconds