Abstract
At the time of the prevalence of coronavirus disease 2019 (COVID-19), pulmonary fibrosis (PF) related to COVID-19 has become the main sequela. However, the mechanism of PF related to COVID (COVID-PF) is unknown. This study aimed to explore the key targets in the development of COVID-PF and the mechanism of d-limonene in the COVID-PF treatment. The differentially expressed genes of COVID-PF were downloaded from the GeneCards database, and their pathways were analyzed. d-Limonene was molecularly docked with related proteins to screen its pharmacological targets, and a rat lung fibrosis model was established to verify d-limonene's effect on COVID-PF-related targets. The results showed that the imbalance between collagen breakdown and metabolism, inflammatory response, and angiogenesis are the core processes of COVID-PF; and PI3K/AKT signaling pathways are the key targets of the treatment of COVID-PF. The ability of d-limonene to protect against PF induced by bleomycin in rats was reported. The mechanism is related to the binding of PI3K and NF-κB p65, and the inhibition of PI3K/Akt/IKK-α/NF-κB p65 signaling pathway expression and phosphorylation. These results confirmed the relationship between the PI3K–Akt signaling pathway and COVID-PF, showing that d-limonene has a potential therapeutic value for COVID-PF.
Highlights
Since 2003, coronavirus has caused multiple major public health events that resulted in global epidemics, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19)
The first five core paths of pulmonary fibrosis (PF) are IL-4 and IL-13 signaling, signaling by ILs, cytokine signaling in immune system, immune system, and antigen processing– cross-presentation. This suggests that the biological pathways of COVID-PF and PF caused by other reasons are different
The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway plays a key role in the occurrence of COVID-PF
Summary
Since 2003, coronavirus has caused multiple major public health events that resulted in global epidemics, such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and coronavirus disease 2019 (COVID-19). Long-term follow-up studies have shown that many survivors of SARS-CoV infection show signs of fibrosis in their lungs [4,5,6]. The clinical manifestations and severity of COVID-19 are similar to those of SARS [9]. The pathological changes in the early lungs of COVID-19 can be manifested as viral interstitial pneumonia, suggesting that it is imperative to start anti-fibrosis treatment in the early clinical stage [11]. Pirfenidone (PFD) is a commonly used drug for the clinical treatment of PF, but it cannot effectively prolong the survival of patients [12, 13]. Due to this lack of therapeutic options, there is a critical need to understand the molecular pathways involved in the development of COVID-PF [16, 17], helping to identify novel targets for therapy and develop new drugs
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