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Review
. 2023 Aug 3:14:1218059.
doi: 10.3389/fphar.2023.1218059. eCollection 2023.

Molecular mechanisms of COVID-19-induced pulmonary fibrosis and epithelial-mesenchymal transition

Peng Pi  1 , Zhipeng Zeng  1 , Liqing Zeng  1 , Bing Han  1 , Xizhe Bai  2 , Shousheng Xu  3
Affiliations
Review

Molecular mechanisms of COVID-19-induced pulmonary fibrosis and epithelial-mesenchymal transition

Peng Pi et al. Front Pharmacol. .

Abstract

As the outbreak of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first broke out in Hubei Province, China, at the end of 2019. It has brought great challenges and harms to global public health. SARS-CoV-2 mainly affects the lungs and is mainly manifested as pulmonary disease. However, one of the biggest crises arises from the emergence of COVID-19-induced fibrosis. At present, there are still many questions about how COVID-19 induced pulmonary fibrosis (PF) occurs and how to treat and regulate its long-term effects. In addition, as an important process of fibrosis, the effect of COVID-19 on epithelial-mesenchymal transition (EMT) may be an important factor driving PF. This review summarizes the main pathogenesis and treatment mechanisms of COVID-19 related to PF. Starting with the basic mechanisms of PF, such as EMT, transforming growth factor-β (TGF-β), fibroblasts and myofibroblasts, inflammation, macrophages, innate lymphoid cells, matrix metalloproteinases and tissue inhibitors of metalloproteinases, hedgehog pathway as well as Notch signaling. Further, we highlight the importance of COVID-19-induced EMT in the process of PF and provide an overview of the related molecular mechanisms, which will facilitate future research to propose new clinical therapeutic solutions for the treatment of COVID-19-induced PF.

Keywords: COVID-19; SARS-CoV-2; epithelial-mesenchymal transition; molecular mechanisms; pulmonary fibrosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Schematic representation of the basic underlying mechanisms of pulmonary fibrosis. Tumor necrosis factor α (TNF-α); Transforming growth factor-β (TGF-β); Interleukin-6 (IL-6); Interleukin-1β (IL-1β); Interleukin-18 (IL-18); Interleukin-4 (IL-4); Interleukin-5 (IL-5); Interleukin-13 (IL-13); Interleukin-17 (IL-17); Interleukin-22 (IL-22); Granulocyte-macrophage colony-stimulating factor (GM-CSF); Interferon γ (INF-γ); Platelet-derived growth factor (PDGF); Fibroblast growth factor (FGF); Vascular endothelial growth factor (VEGF); Insulin-like growth factor-1 (IGF-1); Matrix metalloproteases (MMPs); Tissue inhibitors of metalloproteinases (TIMPs); Extracellular matrix (ECM). Epithelial-mesenchymal transition (EMT); Pathogen-associated molecular pattern (PAMP); Damage-associated molecular pattern (DAMP); Nucleus factor-κB (NF-κB); Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3); Innate lymphoid cells (ILCs); Natural killer cells (NKs); T helper 2 cell (Th-2).
FIGURE 2
FIGURE 2
Schematic representation of the molecular mechanism of COVID-19-induced EMT. Angiotensin-converting enzyme 2 (ACE2); Transmembrane serine protease 2 (TMPRSS2); Transforming growth factor-β (TGF-β); Transforming growth factor-β1 (TGF-β1); Interleukin-8 (IL-8); Interleukin-6 (IL-6); Interleukin-1β (IL-1β); Neutrophil gelatinase-associated lipocalin (NGAL); Protease-activated receptor 4 (PAR 4); Zinc-finger E-box-binding 1 (ZEB1); Urokinase-type plasminogen activator receptor (uPAR); Urokinase plasminogen activator (uPA); Anexelekto (AXL).
FIGURE 3
FIGURE 3
Schematic representation of the molecular mechanism of coronavirus-induced pulmonary fibrosis. Angiotensin-converting enzyme 2 (ACE2); Transmembrane serine protease 2 (TMPRSS2); Inter-leukin-1 (IL-1); Interleukin-1β (IL-1β); Tumor necrosis factor α (TNF-α); Transforming growth factor-β (TGF-β); Interleukin-6 (IL-6); Interferon γ (INF-γ); Interleukin-12 (IL-12); Interleukin-17 (IL-17); Galectin-3 (Gal-3); Triggering receptor expressed on myeloid cells 2 (TREM 2); Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3); T helper 1 cell (Th-1); T helper 17 cell (Th-17); Nitric oxide synthase (NOS); HSP90 (Heat shock protein 90); Epithelial-mesenchymal transition (EMT).
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Grants and funding

This research was funded by the National Key R&D Program of China, grant number No. 2022YFC3600300.