The Role of the Pulmonary Microenvironment in Driving Transition From Systemic Sclerosis to Systemic Sclerosis-Associated Interstitial Lung Disease

Abstract

OBJECTIVE: A common complication in systemic sclerosis (SSc) is the development of SSc-associated interstitial lung disease (SSc-ILD), which has poor prognosis and a high mortality rate. The pulmonary microenvironment may include mediators involved in disease pathogenesis that could be targets for new therapies to reduce SSc-to-SSc-ILD transition. Here, we aimed to identify soluble mediators in bronchoalveolar lavage fluid that would differentiate patients with SSc-ILD from those with SSc only through a systematic review. METHODS: Using a preregistered study protocol, 2 databases (Web of Science, PubMed) were screened for publications between 2000 and 2024 in adult patients (keywords "systemic sclerosis AND biomarker AND [lung lavage OR bronchoalveolar lavage]"). Mediators were metaanalyzed (RevMan) and functionally enriched pathways identified (STRING-DB/G:Profiler). RESULTS: Screening identified 20/82 publications for inclusion into the systematic review, with qualitative syntheses (n = 12) and metaanalyses (n = 5). Thirty different mediators were identified, 17 were available for SSc vs SSc-ILD comparison. Mediators showed strong interconnectedness and were clustered into the following 3 groups: (1) those released from tertiary granules (predominately involved in remodeling of extracellular matrix), (2) those with chemokine receptor binding, and (3) those with antioxidant function. CONCLUSION: Due to the limited number of studies, we were unable to perform a metaanalysis on mediators between SSc and SSc-ILD, highlighting the need for further studies. However, our review strongly highlights the involvement of the pulmonary epithelium in SSc-ILD, contributing to positive feedback between injured epithelial cells and fibroblast activation/fibrosis. Further research into the role of the epithelium is needed to identify novel mechanisms leading to SSc-ILD that could serve as novel pharmacological targets.