Azithromycin lowers inflammation

Dr. Sadrai, a research fellow at Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Department of Ophthalmology, Harvard Medical School, Boston, and her colleagues are among the investigators who are seeking new strategies to suppress corneal inflammation. Corticosteroids currently are the primary therapy. However, their long-term use has the potential for serious complications.

The Schepens researchers in the laboratory of senior scientist Reza Dana, MD, MPH, MSc, evaluated azithromycin because it has been shown to have anti-inflammatory and immunomodulatory properties, although this has not been demonstrated on the ocular surface. Previous studies have demonstrated that macrolides such as azithromycin suppress the NF-KB pathway as well as the release of pro-inflammatory cytokines in vitro.

Looking at total infiltration of CD45, a pan-leukocyte marker, the team observed a significant decrease in inflammation, demonstrated by a 39% reduction relative to control, at day 7 in the corneas treated with azithromycin, Dr. Sadrai said.

A similar reduction was observed in the prednisolone group.

They then analyzed leukocyte subsets important in innate immunity, such as neutrophils, microphages, and dendritic cells. These cells migrate from the cornea to the regional lymph node, where they contact T cells and induce inflammation; the T cells then migrate to the cornea and increase the amount of inflammation.

"Our aim is to suppress this leukocyte mobilization in the cornea to prevent subsequent inflammation," Dr. Sadrai said.

The team found that dendritic cells demonstrated reduced infiltration (35%) at day 7 in the group treated with azithromycin and 40% in the prednisolone-treated group.

To learn what was causing the suppression observed in the mouse corneas, the researchers looked at intercellular adhesion molecule 1 (ICAM-1), which facilitates cell migration to the cornea.

ICAM-1 expression

The Dana laboratory has shown that ICAM-1 expression by normal limbal area of the cornea is undetectable; however, following an inflammatory insult, ICAM-1 expression is significantly upregulated. In their study, the researchers found high expression of ICAM-1 in the limbal area in the vehicle-treated group after cauterization, while expression was decreased in the limbal area of corneas treated with azithromycin.

In other results, the study showed that the expression levels of the anti-inflammatory cytokine IL-10 increased at all time points in eyes treated with azithromycin, compared with vehicle-treated group. The expression of IL-6 varied at different time points.

"These preliminary results were very impressive, and we are continuing this project," Dr. Sadrai said.

"At least in mice, we may use azithromycin as an antibiotic with anti-inflammatory effects in ocular surface inflammation," Dr. Sadrai concluded. "However, some investigations are required to confirm these findings in the clinical population and to define which patient subgroups are most likely to [have a response] to topical azithromycin, in addition to determining the optimal dosage and duration of therapy."

FYI

Reza Dana, MD, MPH, MSc
Phone: 617/912-7404
Dr. Dana did not indicate any financial interest in the subject matter.

Zahra Sadrai, MD
Phone: 617/912-0253
E-mail: z.sadrai@schepens.harvard.edu

Dr. Sadrai has no financial interest in the product mentioned in this article. Inspire Pharmaceuticals provided research support for this study.