C71-06 Transcriptomic Signature of Plasma Cells in Lungs of Silica-exposed Rats

Abstract Introduction Silicosis is a fatal occupational lung disease caused by inhalation of crystalline silica dust. A rapid increase in exposure has been observed among engineered stone (ES) countertop fabricators over the past decade, in part due to insufficient respiratory protection and inadequate enforcement of workplace exposure standards. Despite this growing public health crisis, the pathogenic mechanisms driving and perpetuating fibrosis in silicosis remain poorly understood. Increased numbers of plasma cells have been identified in the lungs of patients with idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), and auto-immune interstitial lung disease (ILD) Here we aim to utilize transcriptomics to identify key cells and signatures involved in pathogenesis of silicosis, with the hypothesis that plasma cells are recruited to the lungs and are contributing to progression of fibrosis through the production of antibodies which drive and perpetuate a pro-fibrotic environment post-exposure. Methodology RNA-seq data from a rat model of silicosis (GSE150689) were analyzed. Male rats were exposed to air or crystalline silica (15mg/m3) 6 hours/day for 5 days. RNA was extracted (miRNeasy Mini Kit, Qiagen) from lung tissue and sequenced (Total RNA Library, Illumina) at post-exposure time intervals 1, 3, 6, 9, 12, and 18 months (n = 5 per treatment group). Reads were aligned against the rat transcriptome (GRCr8) using Bowtie2 and quantified with RSEM. Differential gene expression analysis was performed with DESeq (R v4.5.1). Results Plasma cell-associated genes were significantly upregulated in silica-exposed lungs. In particular, genes associated with plasma cell differentiation and maturation, including Mzb1, Batf, were significantly upregulated (Log2FC1.0 and padj0.05) beginning from 6 months post-exposure. Furthermore, genes associated with formation and secretion of polymeric immunoglobulins in plasma cells, including Jchain, Ighm, Iglc1, Igkv5-24l1, Igkv2-112l2, and Igkvl15, were significantly upregulated (Log2FC1.0 and padj0.05) beginning from 6 months post-exposure. Markers of lung fibrosis increased continuously throughout the post-exposure time interval and peaked at 18 months. Conclusions These findings suggest that plasma cells may be present and active in the lung microenvironment of end-stage silicosis and could potentially contribute to the progression and perpetuation of chronic fibrotic changes in the lungs post-exposure. Further work is needed to determine whether these plasma cells and antibodies are contributing to the pro-fibrotic environment of silicosis. This abstract is funded by: NHLBI K24 HL155884, NHLBI R01 HL137052, VA Merit 1I01BX004767, and TRDRP T30IP0965