Idiopathic pulmonary fibrosis, a condition that causes the formation of scar tissue in the lungs, resulting in shortness of breath, coughing, and gradual respiratory failure, is a life-threatening disease with a mortality rate higher than that of many cancers. Conservative estimates say it affects approximately five million people globally. There is currently no effective drug-based treatment for it.
That may be about to change, thanks to a Greek scientist.
The Unknown Gene Connection
As reported in a new study published in the journal Science Translational Medicine, Dr. Stavros Garantziotis, a Greek professor of Medicine at Duke University and director of the Clinical and Translational Research program at the National Institute of Environmental Health Sciences (one of the US National Institutes of Health), and his team succeeded for the first time in identifying a gene associated with idiopathic pulmonary fibrosis. Building on this new genetic knowledge, they administered a treatment to mice that put the brakes on the disease’s progression, opening the door to effective, personalized therapies for humans in the future.
The need for new treatments is urgent, Dr. Garantziotis told the publication. “Unfortunately, this deadly disease is currently not curable with medication, only with lung transplantation in very specific cases. There are currently three antifibrotic drugs in the US that aim to slow down scarring, but sadly they cannot reverse disease progression. That is why we are trying to understand the causes and biological mechanisms that lead to lung scarring, so we can develop new, effective therapies.”
His team’s efforts now appear to be bearing fruit. The researchers identified a previously unknown mechanism linked to the development of idiopathic pulmonary fibrosis. “We identified a mutation in the gene encoding the immune receptor Tlr5, which is associated with the onset of the disease. Prior studies had shown that Tlr5 plays a role in controlling microbes in the body, and that genetic Tlr5 deficiency is relatively common. One in ten people carries this genetic mutation, known as rs5744168, which renders Tlr5 non-functional. We linked microbial regulation to pulmonary fibrosis and hypothesized that if the body cannot control the bacteria that multiply after each lung injury, such as those caused by smoking, chronic damage and scarring may result.”
Risk Increase of Up to 50%
The researchers analyzed this specific gene in more than 1,000 patients with idiopathic pulmonary fibrosis and in 2,500 individuals without the disease, finding that the Tlr5 receptor mutation appears to raise the risk of developing the condition by 30% to 50%.
Further experiments in mice with pulmonary fibrosis confirmed why Tlr5 deficiency predisposes individuals to the disease. “The body essentially cannot control the bacteria in the lungs,” Dr. Garantziotis noted, adding that “activation of Tlr5 in epithelial cells, the cells lining the bronchi and alveoli in the lungs, stimulates the production of antimicrobial molecules that function as antibiotics. Mice lacking functional Tlr5 but treated with a combination of broad-spectrum antibiotics showed significantly less fibrosis.”
The Bacterial Factor
Human studies in patients with idiopathic pulmonary fibrosis further confirmed the bacterial connection to the Tlr5 gene mutation. “Patients with Tlr5 deficiency had more harmful bacteria in their lungs. This is the first time it has been demonstrated that bacteria can play a role in pulmonary fibrosis, and that a genetic risk factor for the disease operates through its effect on bacteria.”
How can this new and unexpected knowledge be translated into real benefit for patients? “In light of the new findings, we believe that patients with idiopathic pulmonary fibrosis carrying the Tlr5 mutation could benefit from antibiotic therapy. We are essentially talking about targeted treatment within the framework of precision medicine, which could help patients who are more susceptible to bacterial overgrowth. We also know that microbes play a role in the development of other lung conditions. For that reason, we are investigating the role of Tlr5 in diseases such as Chronic Obstructive Pulmonary Disease, where similar mechanisms may be at work.”
Toward New Therapeutic Pathways
Since antibiotics carry side effects and can contribute to microbial resistance, the research team is also exploring alternative therapeutic strategies to target the bacteria that destroy the lungs of pulmonary fibrosis patients. “We used a bacterial protein that activates the Tlr5 receptor and found it to be equally effective as antibiotics in controlling lung bacteria and reducing fibrosis. We are developing pharmaceutical formulations that can deliver the Tlr5-activating protein directly to the epithelial cells of the lung, possibly in inhaled form, in order to maximize therapeutic benefit and minimize potential side effects.”
