As countries around the world compete to develop SARS-CoV-2 (the novel coronavirus that causes COVID-19) vaccines, scientists are trying to understand exactly how it leads to a range of seemingly long-standing symptoms after active viral infections. In a new study, researchers from Osaka University and Osaka Yanye Medical Center in Japan identified an effective treatment for the treatment of fatal inflammatory hyperactivation experienced by many patients with severe COVID-19. The results were recently published in the journal PNAS, entitled "IL-6 trans-induces plasminogen activator inhibitor-1 from vascular endothelial cells in cytokine release syndrome".
Cytokines are a group of small proteins that can enhance or suppress the immune response of our body to diseases such as infection, trauma, and cancer. One of their main roles is to stimulate inflammation and thus initiate the healing process. The problem is that overstimulation of the inflammatory response produces a range of deleterious complications, from asthma to severe autoimmune diseases. One of these complications, called cytokine release syndrome (CRS), is seen in patients who are hyper-immune to microbial infections or trauma and can lead to multiple organ failure or even death.
Sujin Kang of Osaka University, lead author of the paper, said, "Although it is known which cytokines are involved, there is still no specific immunotherapy for CRS, and treatment is limited to supportive care. In order to better understand the molecular mechanisms of CRS pathogenesis, we first studied the cytokine profile in 91 patients (three groups of patients) diagnosed with CRS associated with bacterial sepsis, acute respiratory distress syndrome, or burns."
Strikingly, these three groups of patients had elevated levels of the inflammatory cytokines IL-6, IL-8, IL-10, and MCP-10, as well as a protein called PAI-1, which causes small blood clots in blood vessels throughout the body, including in the lungs. Importantly, increased PAI-1 levels were associated with more severe cases of pneumonia, a common cause of death among COVID-19 patients.
Given that IL-6 is positively correlated with the levels of other cytokines and PAI-1, these researchers concluded that IL-6 signaling is essential for the appearance of CRS after infection or trauma and may play a role in the pathogenesis of COVID-19.
Tadamitsu Kishimoto of Osaka University, the corresponding author of the paper, said, "Studies of cytokine profiles in patients with severe COVID-19 have found that IL-6 increases early in the disease process, resulting in the release of PAI-1 from the blood vessels. Notably, PAI-1 levels were significantly higher in COVID-19 patients with severe respiratory disorders."
Most significantly, however, when severe COVID-19 patients are treated with a human monoclonal antibody drug called tocilizumab (Actemra), this drug blocks IL-6 signaling, rapidly decreases PAI-1 levels, and relieves severe disease symptoms. Therefore, IL-6 signaling blockade may be useful for the treatment of severe respiratory complications in both CRS and COVID-19.
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