Late Breaking Abstract - Lost in Translation: Altered fibroblast translatome in lung fibrosis.

<bold>Background:</bold> Interstitial lung disease (ILD) in patients with Systemic Sclerosis (SSc) is a leading cause of death. Key effector cells are myofibroblasts, which are activated fibroblasts that are known to proliferate and overproduce extracellular matrix (ECM) products. Fibroblast heterogeneity has been identified in SSc-ILD where reduced levels of serine peptidase inhibitor, Kunitz type 2 (SPINT2) was associated with increased ECM, denoting synthetic cells. Thus, it is important to identify the mechanisms that lead to fibroblast expansion and phenotypic-switch. Provocative data from the field of cardiac fibrosis has identified abnormal mRNA translation to regulate fibroblast activation and ECM synthesis. Thus, we hypothesized that in SSc-ILD dysregulated translation is present in fibroblasts. <bold>Methods:</bold> Ribosome profiling also known as ribo-seq, was employed in isolated control and SSc-ILD fibroblasts to provide a picture of the actively translated mRNAs: the <italic>translatome</italic>. <bold>Results:</bold> We reveal a distinct translatome in SSc-ILD compared to age-sex-ethnicity matched controls. Surprisingly, our data revealed that the most upregulated genes at the level of the translatome included NK6 homeobox 1 (NKX6.1) a proliferative transcription factor and eukaryotic initiation factor 4 gamma (EIF4G1) an important constituent of the the eIF4F complex that is essential to initiate protein translation. SPINT2, a marker for healthy fibroblasts was one of the most significantly downregulated genes. In addition, markers for ribosome biogenesis were significantly upregulated in SSc-ILD. <bold>Conclusion:</bold> Our results point at a previously unrecognized mechanism that promotes fibroblast expansion and phenotypic switch in SSc-ILD.