SINGAPORE: A new study from Duke-NUS Medical School has identified a promising new avenue for tackling pulmonary fibrosis, a severe lung condition that progressively impairs breathing. Researchers have discovered that blocking specific proteins in immune cells can significantly reduce lung tissue scarring, offering hope for more effective treatments.
Pulmonary fibrosis is currently managed through therapies that alleviate symptoms and improve patients’ quality of life, but no existing treatment directly targets the underlying disease process. The new findings, published in the European Respiratory Journal, suggest that inhibiting the proteins YAP and TAZ in macrophages—immune cells known to contribute to inflammation and fibrosis—could prevent or even reverse lung scarring.
While macrophages were previously known to drive inflammation and scarring in pulmonary fibrosis, the precise mechanisms were unclear. Researchers at Duke-NUS had earlier established that YAP and TAZ play a role in heart scarring. This led them to investigate whether these proteins also influence lung fibrosis and how their activity shapes disease progression.
YAP and TAZ are part of a crucial molecular pathway that regulates cell growth and repair. However, in a preclinical model of pulmonary fibrosis, the researchers discovered that these proteins also contribute to excessive scarring. By inhibiting YAP and TAZ, the study found that lung regeneration could be promoted in three key ways.
First, reducing excessive immune recruitment by disrupting the connection between YAP, TAZ, and a signalling molecule called CCL2, which attracts immune cells to damaged lung tissue. In pulmonary fibrosis, this excessive immune cell recruitment leads to uncontrolled inflammation and scarring. Blocking YAP and TAZ limits this process, reducing inflammation.
Second, restoring immune balance, as these proteins shift the immune cell ratio towards those that drive inflammation. When YAP and TAZ are blocked, the immune system regains a healthier balance, allowing tissue repair and reducing lung inflammation. Third, interrupting harmful cell communication between macrophages and fibroblasts—cells responsible for tissue repair. Overactive YAP and TAZ cause excessive fibroblast activation, worsening scarring. Inhibiting these proteins breaks this damaging cycle, reducing lung fibrosis.
Lead author Dr Md Masum Mia, Principal Research Scientist at Duke-NUS’ Cardiovascular and Metabolic Disorders Programme, highlighted the significance of these findings, stating that the breakthrough not only deepens 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. The discovery has wider implications, as YAP and TAZ are also implicated in fibrosis affecting other organs, including the heart, liver, and kidneys.
Currently, early-stage clinical trials are investigating therapies targeting YAP and TAZ for cancer treatment, where immune-driven inflammation and scarring are also key factors. The Duke-NUS research team is now exploring whether similar therapeutic strategies could be adapted for pulmonary fibrosis. Associate Professor Manvendra Kumar Singh, the study’s senior author, explained that 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, researchers can gain deeper insights and uncover potential therapeutic targets for treatment. The next steps involve further validating the roles of YAP and TAZ in the disease and confirming the effectiveness of therapies that inhibit these proteins, offering patients better outcomes.
Professor Patrick Tan, Senior Vice-Dean for Research at Duke-NUS, emphasized the potential impact of this research, stating that by focusing on the root causes of fibrosis, the novel therapeutic approach offers the potential not just to manage but to significantly halt or reverse the progression of pulmonary fibrosis. He added that this breakthrough could dramatically improve patient outcomes, reduce long-term healthcare costs, and ultimately enhance life expectancy and quality for sufferers globally.
This study is part of Duke-NUS’ broader efforts to develop biomedical solutions that improve patient outcomes. The research was supported by the National Research Foundation, Singapore, through grants administered by the National Medical Research Council (NMRC) and the Ministry of Health. As scientists continue to explore how targeting YAP and TAZ can be translated into viable treatments, this discovery marks a crucial step towards tackling a devastating disease that affects millions worldwide.