Background/Objectives: A novel patient group with chronic pulmonary fibrosis is emerging post COVID-19. To identify patients at risk of developing post-COVID-19 lung fibrosis, we here aimed to identify systemic proteins that overlap with fibrotic markers identified in patients with idiopathic pulmonary fibrosis (IPF) and may predict COVID-19-induced lung fibrosis. Methods: Ninety-two proteins were measured in plasma samples from hospitalized patients with moderate and severe COVID-19 in Sweden, before the introduction of the vaccination program, as well as from healthy individuals. These measurements were conducted using proximity extension assay (PEA) technology with a panel including inflammatory and remodeling proteins. Histopathological alterations were evaluated in explanted lung tissue. Results: Connecting to IPF pathology, several proteins including decorin (DCN), tumor necrosis factor receptor superfamily member 12A (TNFRSF12A) and chemokine (C-X-C motif) ligand 13 (CXCL13) were elevated in COVID-19 patients compared to healthy subjects. Moreover, we found incrementing expression of monocyte chemotactic protein-3 (MCP-3) and hepatocyte growth factor (HGF) when comparing moderate to severe COVID-19. Conclusions: Both extracellular matrix- and inflammation-associated proteins were identified as overlapping with pulmonary fibrosis, where we found DCN, TNFRSF12A, CXCL13, CXCL9, MCP-3 and HGF to be of particular interest to follow up on for the prediction of disease severity.

Collagen VII is an essential anchoring protein in the basement membrane zone, maintaining the attachment of stratified and pseudostratified epithelia to the underlying interstitial matrix. However, collagen VII is largely unexplored in normal lungs and idiopathic pulmonary fibrosis (IPF), a disease characterized by excessive accumulation of extracellular matrix and aberrant re-epithelialization of fibrotic lung parenchyma. Analysis of collagen VII protein and mRNA encoded by COL7A1 gene in IPF distal lungs demonstrated elevated levels compared with those in normal lungs. To investigate its cellular source and spatial distribution in lung tissue, immunohistochemistry, RNAscope in situ hybridization, and cell culture experiments, in combination with analysis of public transcriptomic data sets were performed. In the IPF lungs, collagen VII was abundant in pathologically remodeled airways and honeycomb cysts, associated with increased basal cell populations. In contrast, in the control lungs, collagen VII was mainly localized in larger airways. RNA sequencing data revealed that epithelial basal cells and KRT5^-/KRT17⁺ aberrant basaloid cells are the primary sources of COL7A1 mRNA expression. Furthermore, COL7A1 mRNA was observed in mesenchymal subsets, and both COL7A1 mRNA and the protein were observed in fibroblast foci, another histopathologic feature of IPF. In vitro, COL7A1 mRNA expression was increased in normal human lung fibroblasts treated with transforming growth factor-β1. These findings suggest that collagen VII could be involved in the process of abnormal re-epithelialization in lung fibrosis.

Background: In this study, we combine proteomics with functional parameters and imaging to examine potential biomarkers that may identify patients at risk of developing persistent lung sequelae following coronavirus disease 2019 (COVID-19).Methods: We performed multiplex profiling of serum and collected clinical data from intensive care unit (ICU)-treated patients with COVID-19 (n=43) at 4 and 10 months post hospitalisation.Results: Four months post discharge, patients with COVID-19 demonstrated lower % predicted forced vital capacity (72.2%versus113% (p<0.0001)) and % predicted forced expiratory volume in 1 s (74.5%versus103% (p5% of lung tissue) on high-resolution computed tomography (HRCT) had higher levels of the proteins lysosomal associated membrane protein-3 (LAMP3) and MMP7 compared with patients with minor (<5%) or no findings on HRCT. Both proteins demonstrated consecutive associations to lung function and parenchymal involvement. Histological evaluation of LAMP3 in lung tissue confirmed LAMP3 localisation to alveolar type 2 cells in more preserved areas of the parenchyma. However, areas of remodelling were devoid of LAMP3 concurrent with the appearance of KRT5+ and KRT17+ basal cells.Conclusion: Despite functional and radiological improvements following COVID-19, persistent upregulation of inflammation and remodelling factors were observed. Similarities in the expression of LAMP3 in COVID-19 and idiopathic pulmonary fibrosis may suggest it as a potential biomarker for chronic lung damage.