Researchers have determined that the enzyme cyclic GMP-AMP synthase (cGAS) plays a pivotal role in driving inflammation and fibrosis in systemic sclerosis-associated interstitial lung disease (SSc-ILD). That’s according to the new study, “Cyclic GMP-AMP Synthase Expression is Enhanced in Systemic Sclerosis-Associated Interstitial Lung Disease and Stimulates Inflammatory Myofibroblast Activation,” recently published in the European Respiratory Journal.
Systemic sclerosis remains a challenging autoimmune disease with limited treatment options for its pulmonary complications. The findings offer a promising new avenue for treatment, according to the study’s authors.
Researchers found that lung tissues and bronchoalveolar lavage fluid from patients with SSc-ILD showed elevated levels of cGAS, along with increased cytokines and type 1 interferons — key markers of immune activation. The study utilized human biospecimens, cultured fibroblasts, precision-cut lung slices and a well-established animal model to investigate the role of cGAS in disease progression.
The research demonstrated that cGAS is not only constitutively active in SSc-ILD fibroblasts but can also be triggered in healthy lung fibroblasts by transforming growth factor-β1 and mechanical stress. This activation leads to the production of inflammatory molecules and α-smooth muscle actin, a marker of myofibroblast activation.
According to researchers, the most promising finding was that a small molecule inhibitor of cGAS was able to significantly reduce these inflammatory responses in both human tissue models and the bleomycin-induced pulmonary fibrosis mouse model.
The study’s authors suggested their findings highlight cGAS as a key driver of the inflammatory myofibroblast phenotype in SSc-ILD. They encouraged further research that targeting cGAS or its downstream signaling pathways could represent a novel and effective therapeutic strategy.
