Year of Publication

2011

Degree Name

Doctor of Philosophy (PhD)

Document Type

Dissertation

College

Pharmacy

Department

Pharmaceutical Sciences

First Advisor

Dr. David Feola

Second Advisor

Dr. Patrick McNamara

Abstract

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.

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