New discovery offers hope in the battle against pulmonary fibrosis

A discovery at Duke-NUS Medical School offers new hope in the battle against pulmonary fibrosis, a debilitating lung condition that progressively makes it harder for patients to breathe. Scientists have pinpointed proteins in immune cells that, when blocked, could significantly reduce lung tissue scarring.

Current treatments primarily manage symptoms and improving quality of life, without addressing the underlying cause of pulmonary fibrosis.

Although macrophages, a type of immune cell, had previously been known to contribute to inflammation and scarring in pulmonary fibrosis, the underlying mechanisms remained unclear. After discovering that two proteins in macrophages-YAP and TAZ-are involved in heart scarring, researchers from the School sought to determine whether these proteins play a similar role in the lungs and to better understand how their activity influences disease progression.

YAP and TAZ are part of a critical molecular pathway that usually helps cells grow and repair. However, in a preclinical model of pulmonary fibrosis, the researchers discovered that these proteins can also contribute to harmful scarring.

In their study, published in the European Respiratory Journal, the researchers found that blocking YAP and TAZ can curb scar formation and restore the immediate environment to one that encourages regeneration in three ways:

Dampening a loud call to arms: YAP and TAZ drive inflammation by amplifying the effect of a molecule called CCL2. Like a homing beacon, this signalling molecule attracts various immune cells to the affected areas of the lungs during injuries. However, when recruited to the lungs in excess, these immune cells can harm the organs by causing uncontrolled inflammation, leading to tissue scarring. Disrupting the connection between the two proteins and CCL2 reduces the number of immune cells recruited, impeding tissue scarring.

Maintaining a healthy immune cell ratio: YAP and TAZ can harm the lungs by increasing inflammatory immune cell levels, amplifying tissue inflammation. When these proteins are removed, immune cells that help to repair and regenerate damaged tissue outnumber their inflammatory counterparts, reducing lung inflammation and allowing the organ to heal more effectively.

Disrupting the proteins' communication with a nearby pathway: These proteins can also exacerbate pulmonary fibrosis by influencing macrophages' interaction with fibroblasts, which are nearby cells that are key to repairing damaged tissue and maintaining organ structure. Unregulated macrophage activity excessively signals fibroblasts to respond to an injury in the lungs, leading to tissue scarring. Inhibiting YAP and TAZ interrupts the communication between macrophages and fibroblasts, reducing damage to the lungs.

Principal Research Scientist Dr Md Masum Mia from Duke-NUS' Cardiovascular and Metabolic Disorders Programme, the study's first author, said of the findings:

"This breakthrough not only deepens our understanding of the specific molecular mechanisms responsible for pulmonary fibrosis, but could also lead to treatments that halt or even reverse lung scarring in the disease."

Paving the way for new treatment options for pulmonary fibrosis

Global early-phase clinical trials for novel therapies that target YAP and TAZ in cancers, which are characterised by immune-driven inflammation and scarring, are underway, and the research team is exploring if such therapies are viable for treating patients with pulmonary fibrosis.

Associate Professor Manvendra Kumar Singh from Duke-NUS' Cardiovascular and Metabolic Disorders Programme, the study's senior author, said of the next steps for the project:

"Pulmonary fibrosis is strongly linked to the unregulated activity of immune and connective tissue cells as well as the loss of epithelial cells. By delving into these interactions that drive tissue scarring, we can gain deeper insights and uncover potential therapeutic targets for treatment. Next, we will further validate the roles of YAP and TAZ in the disease and confirm the effectiveness of therapies that inhibit these proteins, offering patients better outcomes."

In addition to pulmonary fibrosis, YAP and TAZ are also implicated in heart, liver and kidney fibrosis, suggesting that therapies targeting these proteins could offer broader therapeutic potential for a range of fibrotic diseases.

By focusing on the root causes of fibrosis, our novel therapeutic approach offers the potential not just to manage but to significantly halt or reverse the progression of pulmonary fibrosis. This breakthrough could dramatically improve patient outcomes, reduce long-term healthcare costs, and ultimately enhance life expectancy and quality for sufferers globally."

Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS

This new research, part of Duke-NUS' efforts to develop biomedical solutions that improve the lives of patients, is supported by the National Research Foundation, Singapore under the National Medical Research Council (NMRC) Open Fund-Individual Research Grant (MOH-001625) and the Open Fund-Young Individual Research Grant (MOH-001130) and administered by the Singapore Ministry of Health through the NMRC Office, MOH Holdings Pte Ltd.