Potential mechanisms for lung fibrosis associated with COVID-19 infection

Abstract

Pulmonary fibrosis is a sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection that currently lacks effective preventative or therapeutic measures. Post-viral lung fibrosis due to SARS-CoV-2 has been shown to be progressive on selected patients using imaging studies. Persistent infiltration of macrophages and monocytes, a main feature of SARS-CoV-2 pulmonary fibrosis, and long-lived circulating inflammatory monocytes might be driving factors promoting the profibrotic milieu in the lung. The upstream signal(s) that regulates the presence of these immune cells (despite complete viral clearance) remains to be explored. Current data indicate that much of the stimulating signals are localized in the lungs. However, an ongoing low-grade systemic inflammation in long Coronavirus Disease 2019 (COVID-19) symptoms suggests that certain non-pulmonary regulators such as epigenetic changes in hematopoietic stem cells might be critical to the chronic inflammatory response. Since nearly one-third of the world population have been infected, a timely understanding of the underlying pathogenesis leading to tissue remodeling is required. Herein, we review the potential pathogenic mechanisms driving lung fibrosis following SARS-CoV-2 infection based upon available studies and our preliminary findings (Graphical abstract).

Schematic illustration of cellular interaction in COVID-19 PF.

Figure 1.

Diffuse interstitial fibrosis with extensive peribronchiolar metaplasia and inflammatory cell infiltration in COVID-19 lung fibrosis. Hematoxylin and eosin staining of six COVID-19 pulmonary fibrosis explanted lungs.

Figure 2.

Expansion of Keratin 8 positive epithelial cells in COVID-19 lung explants. KRT8 immunostaining. DAB-stained cells indicate KRT8⁺ cells (see arrows). IgG stain is represented in low magnification. DAB=3,3’-diaminobenzidine.