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

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.

Vitamin A Status Modulates Epithelial Mesenchymal Transition in the Lung: The Role of Furin

“…This process, in which differentiated epithelial cells acquire mesenchymal capabilities, is accompanied by ECM changes, rendering a migratory and invasive phenotype. In fact, EMT is an early-stage common factor in several respiratory pathologies associated with pulmonary fibrosis development and lung cancer [ 24 , 26 , 36 , 39 , 40 , 41 ]. In the present work, we have evaluated, in vivo and in vitro, the role of pulmonary vitamin A status on EMT markers and on furin expression, a protein proconvertase that regulates the levels of adhesion molecules and activates proteolytically matrix metalloproteinases, TGF-β factor, and other cytokines and receptors [ 29 , 31 ].…”

1-L Transcription of SARS-CoV-2 Spike Protein S1 Subunit

“…This E3 ubiquitin ligase also regulates ciliary dynamics via the Hedgehog receptor Smoothened (Smo) [146]. Dysregulation of the Hedgehog pathway is one of the molecular mechanisms underlying COVID-19-induced pulmonary fibrosis [147]. During the early phase of ischemic myocardial infarction (MI), WWP1 expression is upregulated in cardiomyocytes located at the infarct border.…”

The Nexus of Inflammation-Induced Epithelial-Mesenchymal Transition and Lung Cancer Progression: A Roadmap to Pentacyclic Triterpenoid-Based Therapies

“…In addition, a retrospective analysis showed that cancer patients had increased pulmonary metastatic lesions 6 months after SARS-CoV-2 infection [99], while no direct oncogenic effect of this virus has been reported to date [101]. The major inducers of EMT produced by COVID-19 are TGF-β, pro-inflammatory cytokines including IL-6 and IL-1β [102], and the urokinase plasminogen activator (uPA), the latter of which is involved in the production of plasmin, which degrades components of the ECM and activates TGF-β [103]. Furthermore, neutrophil extracellular traps (NETs) produced by neutrophils recruited into SARS-CoV-2-infected lungs have also been implicated in EMT induction in lung cancer cells [9].…”

“…Thus, the inflammatory background caused by viral infection may also be involved in the induction of the EMT in lung cancer. More details on the relationship between SARS-CoV-2 infection, tumor progression, and the EMT can be found in recent comprehensive reviews [31,[103][104][105].…”