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Cytokine storm refers to the overactivation of the immune system in response to an infection, leading to excessive or uncontrolled release of proinflammatory cytokines. The term originates from organ transplant failures, where an immune reaction to a transplanted organ or tissue triggers Graft-Versus-Host Disease (GvHD) leading to rejection of the transplant. In infectious diseases, cytokine storm has been reported in response to infection with cytomegalovirus, influenza virus, group A streptococcus and coronaviruses, such as SARS-CoV, SARS-CoV-2 and MERS. In COVID-19, increasing cytokine levels correlate with high viral load, respiratory distress and pulmonary damage.
As a therapeutic target in COVID-19, cytokine storm is problematic as treatment with immunomodulators or anti-cytokine therapies, for example, must strike a balance between reducing the overactive immune response and ensuring maintenance of adequate response for pathogen clearance.
Cytokines are small proteins secreted by immune cells for the purpose of communication and coordinating the body's response to infection and trigger inflammation. A cytokine response is a series of overlapping signaling networks, with redundancies and alternative pathways. An individual cytokine may have multiple, and sometimes unrelated, functions depending on the target cell and the presence/absence of other cytokines. The cytokine family includes chemokines, interferons, interleukins, colony-stimulating factors and tumor necrosis factor.
Infection by SARS-CoV-2 and cytokine storm in the lungs during COVID-19 lead to acute lung injury, characterized by a mononuclear/neutrophilic inflammatory response followed by a chronic fibroproliferative phase. In the acute phase of cytokine storm, levels of acute/early response cytokines, including the cytokines TNF-α, IL-1β and IL-6 and the chemokines CXCL10 and CCL2, dramatically increase. In contrast to SARS-CoV infection, it has been shown the SARS-Cov-2 infection may preferentially upregulate levels of chemokines, rather than cytokines. The large-scale release of these factors causes and maintains an aberrant systemic immune response. Pulmonary inflammation spills over into the systemic circulation, producing persistent hypotension, hypothermia and leucocytosis, which characterize sepsis. This leads to acute respiratory distress syndrome (ARDS) and increased risk of multi-organ failure.
The cytokine storm phenotype also involves hyperactivation of NF-κB signaling pathways by the action of proinflammatory cytokines at their receptors. NF-κB is a transcription factor that regulates the expression of multiple genes, including those for proinflammatory cytokines providing a positive feedback loop. It also regulates the activation, differentiation and effector functions of inflammatory T-cells, and there is evidence that it regulates the activation of inflammasomes.
Additionally, NF-κB signaling is activated by the Angiotensin II (Ang II)- Angiotensin receptor 1 (AT1) axis and in an animal model of SARS-CoV infection, AT1 receptor blockers prevent ARDS. Following viral cell entry, ACE2 is taken into the cell with SARS-CoV, resulting an increase in serum AngII and activation of AT1 receptors. Activation of AT2 receptors has been shown to oppose AT1 signaling with anti-inflammatory properties in some tissues, although the exact mechanism is poorly understood.
Overproduction of cytokines also leads to activation of anticoagulation pathways in COVID-19. Pathways that control thrombin and coagulation homeostasis are dysregulated by inflammation, resulting in the activation of protease-activated receptor 1 (PAR-1) by thrombin. PAR-1 mediates thrombin-induced platelet aggregation as well as cross-talk between coagulation, inflammation and fibrosis; all features of fibroproliferative lung disorders such as COVID-19.
Tocris offers the following scientific literature for Cytokine Storm to showcase our products. We invite you to request* or download your copy today!
*Please note that Tocris will only send literature to established scientific business / institute addresses.