Overlapping Systemic Proteins in COVID-19 and Lung Fibrosis Associated with Tissue Remodeling and Inflammation

Abstract

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.

Keywords: COVID-19; DCN; HGF; IPF; MCP-3; TNFRSF12A; biomarkers; fibrosis.

Figure 1

Elevated protein amount of DCN, TNFRSF12A, MCP-3, HGF, CXCL13 and CXCL9 in plasma from patients with moderate and severe COVID-19 in comparison to healthy subjects. NPX = normalized protein expression. Patients with moderate (n = 8) and severe (n = 8) COVID-19; healthy individuals (n = 7). One-way ANOVA with Tukey’s multiple comparison test. * p < 0.05, ** p < 0.01, *** p < 0.001, **** p < 0.0001, ns=not significant.

Figure 2

The overlapping protein patterns of DCN and POSTN in post-COVID-19 and IPF. In distal lung tissue, the expression of POSTN was mainly localized to the subepithelial regions of bronchioles in healthy (A,D), post-COVID-19 (B,E) and IPF (C,F) patients, enclosed upon magnification in the basement membrane zone (arrow). POSTN was highly expressed in fibroblastic foci in IPF (G,H, encircled area) and in similar structures in post-COVID-19 patients (I,J). Similarly, DCN was found to be intensely expressed in the subepithelial regions of bronchioles (arrowhead) and in vascular adventitia (arrow) (healthy, K–M). Increased DCN expression was also seen in pleura (arrows) and subpleural regions in healthy (N, including HE staining), post-COVID-19 (O, including HE staining) and IPF (P, including HE staining) patients. Scale bar: 500 µm (N–P); 100 µm (A–F, K–M; enlargements N–P); 20 µm (enlargement (D–F), G–J). * = bronchiole; v = vessel.