The role of cytokines and their antagonists in the treatment of COVID‐19 patients

Afshar, Zeinab Mohseni; Barary, Mohammad; Babazadeh, Arefeh; Pirzaman, Ali Tavakoli; Hosseinzadeh, Rezvan; Alijanpour, Amirmasoud; Allahgholipour, Amirreza; Miri, Seyed Rouhollah; Sio, Terence T.; Sullman, Mark J.M.; Carson‐Chahhoud, Kristin; Ebrahimpour, Soheil

doi:10.1002/rmv.2372

Cited by 16 publications

(8 citation statements)

References 137 publications

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“…Since, together with TNF-α, IL-6 is an important component of the cytokine storm induced by SARS-CoV-2 infection (reviewed in [ 18 ]), we also evaluated the secretion of this cytokine in BALs of S-RBD-treated mice. As observed with TNF-α secretion, S-RBD elicited a rapid increase in the levels of IL-6 in BALs from C57 mice, reaching the maximal concentration 4 h after nebulization (baseline: 68.5 ± 19.2 pg/mL; 2 h post nebulization: 229.1 ± 16.9 pg/mL; 4 h post-nebulization: 338.9 ± 17.4 pg/mL).…”

Section: Resultsmentioning

confidence: 99%

Jacareubin inhibits TLR4-induced lung inflammatory response caused by the RBD domain of SARS-CoV-2 Spike protein

et al. 2022

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Background COVID-19, the disease caused by SARS-CoV-2 virus infection, has been a major public health problem worldwide in the last 2 years. SARS-CoV-2-dependent activation of innate immune receptors contributes to the strong local and systemic inflammatory reaction associated with rapid disease evolution. The receptor-binding domain (RBD) of Spike (S) viral protein (S-RBD) is essential for virus infection and its interacting molecules in target cells are still under identification. On the other hand, the search for accessible natural molecules with potential therapeutic use has been intense and remains an active field of investigation. Methods C57BL6/J (control) and Toll-like receptor (TLR) 4-deficient ( Lps del ) mice were nebulized with recombinant S-RBD. Tumor Necrosis Factor-alpha (TNF-α) and Interleukin (IL)-6 production in bronchoalveolar lavages (BALs) was determined by enzyme-linked immunosorbent assay (ELISA). Lung-infiltrating cells recovered in BALs were quantified by hematoxylin–eosin (H&E) stain. In selected groups of animals, the natural compound Jacareubin or dexamethasone were intraperitoneally (ip) administered 2 hours before nebulization. Results A rapid lung production of TNF-α and IL-6 and cell infiltration was induced by S-RBD nebulization in control but not in Lps del mice. Pre-treatment with Jacareubin or dexamethasone prevented S-RBD-induced TNF-α and IL-6 secretion in BALs from control animals. Conclusions S-RBD domain promotes lung TNF-α and IL-6 production in a TLR4-dependent fashion in C57BL6/J mice. Xanthone Jacareubin possesses potential anti-COVID-19 properties that, together with the previously tested anti-inflammatory activity, safety, and tolerance, make it a valuable drug to be further investigated for the treatment of cytokine production caused by SARS-CoV-2 infection. Supplementary Information The online version contains supplementary material available at 10.1007/s43440-022-00398-5.

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Section: Resultsmentioning

confidence: 99%

Jacareubin inhibits TLR4-induced lung inflammatory response caused by the RBD domain of SARS-CoV-2 Spike protein

et al. 2022

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“…This hyperinflammatory condition is characterized by the uncontrolled release of pro-inflammatory cytokines, leading to significant complications. High levels of numerous crucial pro-inflammatory cytokines, such as interleukin-1 (IL-1), IL-2, IL-6, tumor necrosis factor-α, interferon (IFN)-γ, IL-10 and so on, have been found in severe COVID-19 ( 24 , 25 ). Moreover, the hyperproduction of IL-10 and IL-6 have been linked to cytokine storm-induced mortality in fatal thrombocytopenia syndrome and severe and critically ill COVID-19 patients ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Case report: unprecedented case of infantile cerebral infarction following COVID-19 and favorable outcome

Zheng,

Chen,

et al. 2024

Front. Immunol.

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The 2019 novel coronavirus, SARS-CoV-2, was highly prevalent in China as of December 2022, causing a range of symptoms, predominantly affecting the respiratory tract. While SARS-CoV-2 infection in children is generally mild, severe cases, especially in infants, are rare. We present a case of a previously healthy 7-month-old infant who developed cerebral infarction and coagulation dysfunction three days after COVID-19 onset. Clinically, the infant had weakness in the left limbs and pinpoint bleeding spots. A cranial magnetic resonance imaging showed ischemic strokes in the right basal ganglia and thalamus. Laboratory tests indicated thrombocytopenia and coagulation dysfunction. Inflammatory cytokines like interleukin-10 were elevated, with increased CD3+, CD4+, and CD8+ T lymphocytes but decreased CD3- CD16+ CD56+ natural killer cells. Treatment included mannitol, dexamethasone, oral aspirin, and vitamins B1 and B6 for reducing intracranial pressure, antiinflammation, anticoagulation, and nerve support, respectively. During the recovery phase, rehabilitation therapy focused on strength training, fine motor skills, and massage therapy. The infant gradually improved and successfully recovered. While rare, such cases can lead to severe complications. These combined efforts were instrumental in achieving significant functional recovery in the patient, demonstrating that even in severe instances of pediatric cerebral infarction due to COVID-19, positive outcomes are attainable with early and comprehensive medical response.

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“…This finding is in line with previously published mechanisms of type-I and type-II interferons shown for acute influenza A virus infection [ 38 ] and HSV-2 virus infection [ 39 ], where the orchestrated stimulation and release of type-I and -II IFNs resulted in APC activation and an adaptive type 1 T helper (Th1) response. Mainly type-II IFN has been identified as the main driver of the cytokine storm in COVID-19 patients [ 40 ] and is associated with cytokine dysfunction of secondary organs [ 41 ].…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Gene Expression Analysis Reveals Unique Genes Signatures of Epithelial Reorganization in Primary Airway Epithelium Induced by Type-I, -II and -III Interferons

et al. 2022

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Biosensors such as toll-like receptors (TLR) induce the expression of interferons (IFNs) after viral infection that are critical to the first step in cell-intrinsic host defense mechanisms. Their differential influence on epithelial integrity genes, however, remains elusive. A genome-wide gene expression biosensor chip for gene expression sensing was used to examine the effects of type-I, -II, and -III IFN stimulation on the epithelial expression profiles of primary organotypic 3D air-liquid interface airway cultures. All types of IFNs induced similar interferon-stimulated genes (ISGs): OAS1, OAS2, and IFIT2. However, they differentially induced transcription factors, epithelial modulators, and pro-inflammatory genes. Type-I IFN-induced genes were associated with cell–cell adhesion and tight junctions, while type-III IFNs promoted genes important for transepithelial transport. In contrast, type-II IFN stimulated proliferation-triggering genes associated and enhanced pro-inflammatory mediator secretion. In conclusion, with our microarray system, we provide evidence that the three IFN types exceed their antiviral ISG-response by inducing distinct remodeling processes, thereby likely strengthening the epithelial airway barrier by enhancing cross-cell-integrity (I), transepithelial transport (III) and finally reconstruction through proliferation (II).

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The role of cytokines and their antagonists in the treatment of COVID‐19 patients

Cited by 16 publications

References 137 publications

Jacareubin inhibits TLR4-induced lung inflammatory response caused by the RBD domain of SARS-CoV-2 Spike protein

Jacareubin inhibits TLR4-induced lung inflammatory response caused by the RBD domain of SARS-CoV-2 Spike protein

Case report: unprecedented case of infantile cerebral infarction following COVID-19 and favorable outcome

Genome-Wide Gene Expression Analysis Reveals Unique Genes Signatures of Epithelial Reorganization in Primary Airway Epithelium Induced by Type-I, -II and -III Interferons

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