Grants and Contracts Details
Description
Cystic fibrosis (CF) causes progressive lung disease that is life threatening due to repeated bacterial
infections causing chronic inflammation that leads to lung damage. Recently, a subset of macrophages have
been defined as alternatively activated (M2) cells that have different functions than the classically activated
subtype (M1) involved in inflammation and phagocytosis. M2 cells playa role in tissue repair, pulmonary
remodeling, and drive helper T-cell and anti-inflammatory processes. Because M2 cells orchestrate the
secretion of extracellular matrix proteins post-inflammation, they could playa critical role in the progression
of fibrosis associate with CF. Azithromycin (AZM) is an antimicrobial agent that has been shown to also alter
inflammation and improve morbidity in patients with CF. We recently demonstrated in a set of in vitro that
AZM polarizes macrophages toward characteristics of the M2 subtype. The hypothesis of this project is that
in mice infected with Pseudomonas aeruginosa, AZM exposure polarizes the macrophage population toward
an M2 phenotype, thereby decreasing the inflammatory response but increasing extracellular matrix (ECM)
protein production. We will utilize a P. aeruginosa mouse pulmonary infection model, as normal BALB/c
mice will be exposed to sub-inhibitory concentrations of AZM. Mice receiving AZM will be infected with PA
intratracheally and sacrificed at post-infection timepoints. The effect of the drug on macrophage phenotype
(M1 vs. M2) and function in the lung digests will be compared to infected controls. Phenotype wil be
examined by evaluating surface marker expression using flow cytometry, and function will be assessed by
examining cytokine production, inducible nitric oxide synthase (M1 )/arginase (M2) expression, bacterial
clearance rate, and ECM production. While AZM therapy may be beneficial in the short-term, M2
polarization from chronic AZM use may lead to an eventual increase in fibrosis and override any early
benefits. A better understanding of macrophage function in the CF patient will delineate the activation,
- potential destruction, and the azithromycin-induced alteration of host defense function. With increases in the
development of antimicrobial resistance in organisms such as Pseudomonas, identification of alternative
therapeutic targets that alter or enhance the host's response to infection is of a high priority. This could lead
to advances in treatment of bacterial infections in both CF patients and in the general patient population.
Status | Finished |
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Effective start/end date | 10/1/07 → 9/30/09 |
Funding
- Society of Infectious Diseases Pharmacists: $20,000.00
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