Targeting the Fibrotic Phase of Diffuse Alveolar Damage: Early Pathways for Post-COVID-19 pulmonary fibrosis

<bold>Introduction:</bold> Post-COVID-19 fibrosis affects some patients after the acute phase, activating transcripts that drive extracellular matrix(ECM) deposition and tissue remodeling. Understanding the molecular pathways in early fibrosis is essential to prevent post-COVID-19 fibrotic complications. <bold>Aims:</bold> To identify transcripts and molecular pathways involved in post-COVID-19 fibrosis. <bold>Methods:</bold> Minimally invasive autopsies were performed on 47 +COVID-19 patients from May to July 2020. Clinical data were collected, and histopathological analysis with PicroSirius Red staining was performed. RNA-Seq was conducted on 32 COVID-19 samples and 6 control (non-neoplastic lung tissue), followed by bioinformatic analysis, including DESeq2 for differential expression(DE), GSEA and Enrichr. <bold>Results:</bold> Patients had a mean age of 67yo. Histological analysis showed both acute and chronic changes: 1) acute fibrinous organization, alveolar hemorrhage, hyaline membranes, and thrombus formation; and 2) fibrotic pattern in 87% with septal thickening and significantly higher collagen deposition than controls(p<0.05). DESeq2 analysis identified 1,592 DE genes(padj<0.01). Functional enrichment analysis revealed enrichment in collagen biosynthesis and ECM organization (p<0.001), while GSEA highlighted epithelial-mesenchymal transition and angiogenesis(p<0.001). <bold>Conclusions:</bold> The fibrotic phase of diffuse alveolar damage in COVID-19 results from activated molecular pathways that drive parenchymal remodeling and ECM deposition, indicating potential biomarkers and therapeutic targets for preventing post-COVID fibrosis. <bold>Funding:</bold> FAPESP 21/09024-6; 23/10184-3; 20/13370-4; 22/02821-0; CNPq 310415/2021-7.