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Review
. 2024 Jul 18;11(7):14.
doi: 10.3390/medicines11070014.

Cytokine Storm in COVID-19: Insight into Pathological Mechanisms and Therapeutic Benefits of Chinese Herbal Medicines

Qingyuan Yu  1   2 , Xian Zhou  3 , Rotina Kapini  3   4 , Anthony Arsecularatne  3   5 , Wenting Song  1 , Chunguang Li  3 , Yang Liu  3 , Junguo Ren  1 , Gerald Münch  3   5 , Jianxun Liu  1 , Dennis Chang  3
Affiliations
Review

Cytokine Storm in COVID-19: Insight into Pathological Mechanisms and Therapeutic Benefits of Chinese Herbal Medicines

Qingyuan Yu et al. Medicines (Basel). .

Abstract

Cytokine storm (CS) is the main driver of SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) in severe coronavirus disease-19 (COVID-19). The pathological mechanisms of CS are quite complex and involve multiple critical molecular targets that turn self-limited and mild COVID-19 into a severe and life-threatening concern. At present, vaccines are strongly recommended as safe and effective treatments for preventing serious illness or death from COVID-19. However, effective treatment options are still lacking for people who are at the most risk or hospitalized with severe disease. Chinese herbal medicines have been shown to improve the clinical outcomes of mild to severe COVID-19 as an adjunct therapy, particular preventing the development of mild to severe ARDS. This review illustrates in detail the pathogenesis of CS-involved ARDS and its associated key molecular targets, cytokines and signalling pathways. The therapeutic targets were identified particularly in relation to the turning points of the development of COVID-19, from mild symptoms to severe ARDS. Preclinical and clinical studies were reviewed for the effects of Chinese herbal medicines together with conventional therapies in reducing ARDS symptoms and addressing critical therapeutic targets associated with CS. Multiple herbal formulations, herbal extracts and single bioactive phytochemicals with or without conventional therapies demonstrated strong anti-CS effects through multiple mechanisms. However, evidence from larger, well-designed clinical trials is lacking and their detailed mechanisms of action are yet to be well elucidated. More research is warranted to further evaluate the therapeutic value of Chinese herbal medicine for CS in COVID-19-induced ARDS.

Keywords: COVID-19; acute respiratory distress syndrome; curcumin; cytokine storm; integrative Chinese medicines.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Pathogenesis of COVID-19 ARDS. The SARS-CoV-2 enters the upper respiratory tract and infects the ciliated cells in the area, predominantly in the nasopharynx. In most individuals, the virus is cleared at this stage by the corresponding inflammatory and immune response, but in some individuals with diminished or absent responses, the virus continues to spread. The SARS-CoV-2 will spread down the bronchoalveolar tree, ultimately ending up in the alveoli where it infects alveolar type 2 (AT2) cells. This results in the release of cytokines and chemokines, activating and disrupting the endothelial layer, which release more chemoattractant, leading to the migration of circulating immune cells. Monocytes, in addition to resident alveolar macrophages, migrate to the site of infection but become infected and undergo pyroptosis, releasing large amounts of pro-inflammatory cytokines. Neutrophils create neutrophil extracellular traps (NETs), in a process known as NETosis, ultimately creating microthrombi. In addition, neutrophils and CD16+ T cells release pro-inflammatory proteins, contributing to the pulmonary hyperinflammation that precedes ARDS.
Figure 2
Figure 2
The JAK-STAT signalling pathways in CS and cell survival. TNF-α binds to TNF receptor 1 to initiate the downstream of protein molecules. The TNFR1–associated death domain protein (TRADD) interacts with TRAF 2 to activate caspase 10 and 3 and lead to apoptosis. Fas-associated death domain (FADD) interacts with RAIDD protein to activate caspase 8 that also activates 3 (and 6 and 7 in some cases) to induce apoptosis. TRAF 2 and TRADD also activate IKK phosphorylation to produce NF-κB dimers via M1KKS and NIK. IL-6 similarly activates NF-κB dimers as with the JAK/STAT3 pathway to express inflammatory genes. IFN-γ follow suit by binding to IFNGR to transduce JAK2/STAT1 pathway to contribute to the initiation of SIRs via pro-inflammatory cytokines.
Figure 3
Figure 3
Priming and activation of the NLRP3 inflammasome. Priming of the NLRP3 inflammasome typically results from pathogen- or damage-associated molecular pattern interaction with toll-like receptors (TLRs), IL-1β binding to IL-1 receptor or TNF binding to TNF receptor. This ultimately leads to NF-κB nuclear translocation through a signalling cascade, which leads to the production of NLRP3, caspase 1 (CASP1), pro-IL-1β and pro-IL-18. A variety of intracellular and extracellular events can activate the NLRP3 inflammasome, including viral invasion, Ca2+ influx or K+ efflux, ROS, or oxidised mitochondrial DNA. These stimuli increase the amount of inactive NLRP3, which can then oligomerize with ASC, NEK7 and CASP1 to form the NLRP3 inflammasome. The NLRP3 inflammasome can then convert pro-IL-1β and pro-IL-18 to IL-1β and IL-18 and catalyse the formation of the gasdermin D N-terminal pores, leading to the release of pro-inflammatory cytokines and initiation of pyroptosis, respectively.
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Grants and funding

This work was supported by Science and technology Innovation Project of China Academy of Chinese Medical Sciences (CI2021A04601). Zhou X is supported by the Research Support Program Fellowship, Western Sydney University.

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