Antibiotic Azithromycin Lessens Fibrosis, Promotes Death of IPF Fibroblasts, Study Reports

The antibiotic azithromycin (AZT), frequently prescribed for fighting bacterial infections, has anti-fibrotic effects and promotes the death of fibroblasts — cells promoting fibrosis, or scarring — in people with idiopathic pulmonary fibrosis (IPF), a new study shows.

These findings suggest the potential of AZT as a therapeutic option for IPF.

The study, “αAzithromycin has enhanced effects on lung fibroblasts from idiopathic pulmonary fibrosis (IPF) patients compared to controls,” was published in the journal Respiratory Research.

In IPF, excessive wound healing leads to scarring and increased stiffness of lung tissue, impairing a person’s ability to breathe. Fibroblasts — the cells that synthesize and secrete collagen and extracellular matrix (ECM) components, and are essential for the normal structure and support of tissues — are considered to be the main contributors to fibrosis development.

Despite recent treatments that slow down disease progression, people with IPF ultimately require a lung transplant at later stages. Thus, new treatment strategies are urgently needed to help these patients.

The antibiotic AZT is commonly prescribed in the clinic, and its longterm use in people with chronic obstructive pulmonary disease (COPD), asthma, and cystic fibrosis is linked with improved lung function. Additionally, studies have shown that azithromycin treatment decreases IPF mortality associated with acute exacerbations. In the bleomycin rodent model for lung fibrosis, AZT was shown to have anti-fibrotic effects.

Research also has suggested that fibroblasts from IPF patients are impaired in a cells’ natural cleaning system, called autophagy. AZT also has been reported to reduce autophagy.

Now, scientists at University of Bern, in Switzerland, evaluated whether IPF fibroblasts’ response to AZT differs from that of fibroblasts from healthy people. To test this, they obtained fibroblasts from healthy lung tissue from cancer patients undergoing surgery, and IPF fibroblasts from diagnostic biopsies.

Using these cells in laboratory cultures, the researchers stimulated fibrosis by providing transforming growth factor-beta (TGF-beta), the most well-known pro-fibrotic signaling protein, to cells.

They observed that pro-fibrotic markers — like collagen type Iα1 (Col1A1) and fibronectin — and proteins from the extracellular matrix were elevated with TGF-beta in both cell types.

In turn, treatment of the cells with AZT reduced the levels of the Col1A1 gene in both healthy and IPF cells. However, unlike control (healthy) fibroblasts, IPF cells showed a significant reduction of Col1A1 protein and fibronectin after AZT treatment.

The researchers also found that the protein αSMA, produced by myofibroblasts — the cells responsible for the synthesis and buildup of scar tissue — was reduced in IPF fibroblasts after AZT treatment.

The team then assessed the level of autophagy in both control and IPF fibroblasts, and found that AZT treatment reduced autophagy in both cells. This reduction was found to a greater extent in the cells isolated from IPF patients, as shown by measuring the accumulation of autophagic markers LC3I and LC3II.

Next, researchers evaluated toxicity and cell death induced by azithromycin treatment. Healthy fibroblasts treated with increasing concentrations of AZT showed no signs of cytotoxicity — destruction of healthy living cells around the target cells. However, in certain IPF fibroblasts, the team saw higher levels of LDH, a marker of cell toxicity.

Azithromycin also led to a significant increase in early apoptosis — programmed cell death — in IPF fibroblasts compared with healthy cells.

“Our results suggest that some IPF fibroblasts are more sensitive to AZT treatment than control fibroblasts,” the researchers said.

Genetic analysis of AZT-treated fibroblasts revealed alterations in lysosomal genes. Additional experiments showed that lysosomes — cell organelles that degrade and recycle unwanted material in the cell — accumulated in AZT-treated cells, suggesting an effect of AZT in these “degrading” factories.

“Our study shows that AZT has anti-fibrotic and pro-apoptotic effects on primary fibroblasts and that these effects are enhanced in IPF fibroblasts compared to control fibroblasts,” the researchers said.

These findings “may stimulate new treatment strategies for IPF patients, but need to be tested in controlled clinical trials,” the team added.