Extracellular vesicle-encapsulated micro-rnas in idiopathic pulmonary fibrosis: a pilot study

SESSION TITLE: Diffuse Lung Disease: Reimagining the Standard of Care SESSION TYPE: Rapid Fire Original Inv PRESENTED ON: 10/10/2023 12:00 pm - 12:45 pm PURPOSE: Growing evidence suggests plasma extracellular-vesicle encapsulated microRNAs (EV-miRNAs) regulate signaling networks that promote lung fibrosis and may be modifiable drivers of idiopathic pulmonary fibrosis (IPF). However, no prior studies have characterized the role of total plasma EV-miRNAs in IPF. We aimed to evaluate associations of plasma EV-miRNAs with IPF pathology and markers of IPF severity in a case-control study of adults with IPF. METHODS: This single-center case-control study enrolled adults with IPF who were diagnosed according to established clinical practice guidelines. Control participants with no known lung disease were recruited from family members of adults with IPF and were matched on age and sex. Plasma EV-miRNAs were measured in all participants using a non-targeted approach. EV-miRNAs that were detectable in ≥80% of study samples were retained for analyses. Spirometry was collected in all adults with IPF. Associations of IPF case status and the forced vital capacity (FVC, in liters) with plasma EV-miRNAs were modeled in separate linear regression models adjusted for age, sex, smoking status, and smoking pack-years. Benjamini-Hochberg false discovery rate (FDR) correction was used to account for multiple comparisons. Biological functions of significant EV-miRNAs were explored using pathway analyses. RESULTS: This pilot study included 10 adults with IPF and 5 control participants. The study population mean age was 68 ± 6.6 years, 12 (80%) were men, and 12 (80%) were White. In total, 872 EV-miRNAs were detected in at least 80% of plasma samples. IPF case status was associated with increased expression of 1 plasma EV-miRNA (miR-346) and decreased expression of 3 EV-miRNAs (miR-4681, miR-3652, miR-6880-5p) (FDR q<0.05). Among adults with IPF, higher levels of 20 EV-miRNAs and lower levels of 2 EV-miRNAs were associated with lower FVC (FDR q<0.05). A biological pathway analysis showed the EV-miRNAs that were associated with FVC interact with genes that modulate the extracellular matrix, fatty acid metabolism, and the TGF-beta signaling pathway (FDR q<0.05), which are heavily implicated in IPF pathogenesis. CONCLUSIONS: Adults with IPF exhibited differential expression of plasma EV-miRNAs that were associated with markers of IPF severity. Plasma EV-miRNAs may represent easily accessible mechanistic biomarkers of IPF pathology. Future research should determine if plasma EV-miRNAs can be used to screen for IPF and should provide a detailed characterization of the role of EV-miRNAs in IPF to maximize potential to re-engineer EVs into vehicles for IPF treatment. CLINICAL IMPLICATIONS: Plasma EV-miRNAs may represent novel mechanistic biomarkers of IPF pathology that may help optimize IPF diagnosis and may be targetable factors for IPF treatment. DISCLOSURES: No disclosure on file for Andrea Baccarelli No disclosure on file for Matthew Baldwin No relevant relationships by Shannon Benesh No relevant relationships by Christopher Depender No relevant relationships by Christina Eckhardt Consultant relationship with Rejuvenation Technologies Inc Please note: 11/11/2022 - present Added 04/13/2023 by Christine Kim Garcia, source=Web Response, value=Ownership interest Consultant relationship with Rejuveron Telomere Therapeutics AG Please note: 1/16/2023 - present Added 04/13/2023 by Christine Kim Garcia, source=Web Response, value=Consulting fee grant to institution relationship with Boehringer Ingelheim Please note: 9/1/20 - present Added 04/13/2023 by Christine Kim Garcia, source=Web Response, value=Grant/Research Support No relevant relationships by Gabriela Jackson No relevant relationships by Claire McGroder No relevant relationships by Fang Wang No relevant relationships by Haotian Wu No relevant relationships by Da Zhang