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Review
. 2023 Mar:116:109418.
doi: 10.1016/j.intimp.2022.109418. Epub 2022 Nov 4.

Lung fibrosis: Post-COVID-19 complications and evidences

Rishabh Hirawat  1 , Namrata Jain  1 , Mohd Aslam Saifi  1 , Mahesh Rachamalla  2 , Chandraiah Godugu  3
Affiliations
Review

Lung fibrosis: Post-COVID-19 complications and evidences

Rishabh Hirawat et al. Int Immunopharmacol. 2023 Mar.

Abstract

Background: COVID 19, a lethal viral outbreak that devastated lives and the economy across the globe witnessed non-compensable respiratory illnesses in patients. As been evaluated in reports, patients receiving long-term treatment are more prone to acquire Pulmonary Fibrosis (PF). Repetitive damage and repair of alveolar tissues increase oxidative stress, inflammation and elevated production of fibrotic proteins ultimately disrupting normal lung physiology skewing the balance towards the fibrotic milieu.

Aim: In the present work, we have discussed several important pathways which are involved in post-COVID PF. Further, we have also highlighted the rationale for the use of antifibrotic agents for post-COVID PF to decrease the burden and improve pulmonary functions in COVID-19 patients.

Conclusion: Based on the available literature and recent incidences, it is crucial to monitor COVID-19 patients over a period of time to rule out the possibility of residual effects. There is a need for concrete evidence to deeply understand the mechanisms responsible for PF in COVID-19 patients.

Keywords: COVID-19; Epithelial-mesenchymal transition; Pulmonary fibrosis; TGF-β; WNT; YAP/TAZ.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1
Fig. 1
An overview of the EMT pathway. The alveolar injury results in decreased expression of ACE2 receptors, resulting microcytic injuries in epithelial cells. Epithelial injury can increase the expression of TGF-β and force reprogramming of the ZEB-1 gene to alter characteristic function of healing factors. Genetic reprogramming along with altered functions of the growth factors increase motility of epithelial cells and helps in their transition into mesenchymal subtype that ultimately increases the risk of pulmonary fibrosis.
Fig. 2
Fig. 2
TGF-β signalling pathway activation. The damaged alveolar epithelial cells stimulate TGF-β signalling, during this process the latent TGF-β escapes the LLC complex and binds with the TGF-β1 receptor which activates SMAD along the way interferes with the collagen genes like COL1A1, COL1A3, TIMP1 and increases the collagen deposition leading to varied ECM depositions.
Fig. 3
Fig. 3
A simplified diagrammatic representation of WNT signalling pathway: During inactive state β-catenin and Cadherin form a conjugate that combine with other factors like Casein kinase 1 CK1, Glycogen synthase kinase 3 GSK3, APC, Axin, which are degraded with the help of a β-trcp protein. Apparently, in the active phase the WNT signalling helps β-catenin to transduce from the membrane while it forms the complex at the same time stimulation of Dishevelled protein results in inhibition of GSK3 and frees the β-catenin, this unbundled β-catenin accumulates in the cytoplasm and target genes like MMP7, MMP14, RAS, FSP1 and alters their mechanism leading to myofibroblast activation causing excess ECM deposition.
Fig. 4
Fig. 4
YAP/TAZ Signalling pathway. In the active state, a kinase complex is formed between LATS1/2 and MST1/2 via stimulation of MOB, which inhibits the YAP/TAZ and further initiates nucleus transduction where YAP and TAZ bind with RUNX, TEAD whilst upregulating targeted genes CTGF, AXL, BIRC5, AREG, JAG1, that activates myofibroblasts ultimately exceeds ECM deposition.
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Further reading

    1. Nusair S. Abnormal carbon monoxide diffusion capacity in COVID-19 patients at time of hospital discharge. Eur. Respir. J. 2020;56 - PMC - PubMed