In this newsletter, we continue to explore how Cellix’s VenaFlux Solutions can help researchers to study mechanisms involved in the development of severe COVID-19 disease such as:
Severe systemic inflammation due to a cytokine storm: this newsletter focuses on this aspect and gives information on respective model and solution.
Endothelial Dysfunction: click here for previous blog.
Microvascular Thrombosis: click here for previous blog.
Mounting evidence has demonstrated that severely ill COVID-19 patients presented with elevated levels of cytokines such as serum IL-1β, IL-6, IL-10, suggesting the involvement of a cytokine storm. Cytokine storms represent an exaggerated immune response characterized by over-production of pro-inflammatory cytokines and chemokines such as IFN-γ, TNF-α, IL-6, IL-1β, IL-18, CXCL8 and CXCL10.
![A rash with red blotchy skin; a common side effect of COVID-19 often referred to as "COVID toe", [2].](https://static.wixstatic.com/media/a27d24_d512dca25271418faed5ed4ee6d2530b~mv2.jpg/v1/fill/w_100,h_80,al_c,q_80,usm_0.66_1.00_0.01,blur_2,enc_auto/a27d24_d512dca25271418faed5ed4ee6d2530b~mv2.jpg)
While an adequate release of cytokines is critical for the body's defence against viral infection, uncontrolled and aberrant immune system activation can lead to organ injury. Timely control of hyper-inflammatory response is crucial to prevent multi-organ dysfunction accompanying COVID-19.
A new study led by Chinese researchers in collaboration with UCLA's Dr. Yibin Wang [3] has shown that people hospitalized with COVID-19 who took statin drugs were less likely to die and less likely to need mechanical ventilation than those who did not take the cholesterol-lowering drugs. Hospitalized patients taking statins had a 5.2% mortality rate, compared to a 9.4% mortality rate in patients not taking statins - from two groups of COVID-19 patients with matching clinic characteristics except statin usage. Statin use was also linked to lower levels of inflammation, and a lower incidence of acute respiratory distress syndrome and admission to intensive care units.
Statins are potent lipid-lowering agents that act on the mevalonate pathway by inhibiting HMG-CoA the rate-limiting enzyme for cholesterol synthesis. It has been previously shown that statins have anti-inflammatory properties that are independent of their lipid lowering capability. For example, patients with cardiovascular disease or patients prior to surgery who were receiving statin therapy had a lower incidence of sepsis and with fewer progressing to severe sepsis and death.
Cellix's VenaFlux Solutions enable researchers to model inflammation in-vitro by recreating the physiological conditions of human blood vessels providing researchers with a controlled experimental set-up to develop treatments which reduce side effects in COVID-19.
Cellix recommended products for microvascular inflammation studies:
In our model, engineered microcapillaries of the Vena8 Fluoro+ biochip can be coated with adhesion molecules typically expressed on stimulated endothelial cells and adhesion of leukocytes flowing through through the microcapillaries under shear stress can be quantified.
To mimic anti-inflammatory effects of statins in COVID-19, mononuclear cells were isolated from six healthy donors. Monocytes were allowed to adhere to the culture vessels before B-cells were removed from the T-cell population using nylon wool adhesion. T-cells were then co-cultured in the presence of monocytes. Cells were treated with 10 nM meva-, lova- or simvastatin dissolved in ethanol (0.1% v/v final) or prava- or fluvastatin dissolved in water.
Cells were then stimulated with 2 µg/mL lipopolysachharide (LPS) and 20 µg/mL peptidoglycan G (PepG) to model inflammation. Control cells were treated with 0.1% v/v ethanol ± LPS/PepG and incubated a humidified 37°C incubator containing 5% CO2 for 18 hrs. Isolated T cells were pumped into the rhICAM-1 and BSA coated microcapillaries of the Vena8 Fluoro+ biochip under venous shear stress of 0.5 dyne/cm2 for 5 min and the number of adherent cells was quantified for each experimental condition. Co-cultured T cells stimulated with LPS/PepG caused a statistically significant increase in adhesion to rhICAM-1 compared to the unstimulated control. Our results showed that LPS/PepG stimulated cells treated with all statins (pravastatin, fluvastatin, mevastatin, lovastatin and simvastatin) caused a statistically significant reduction in adhesion when compared to the LPS/PepG stimulated control and therefore a therapeutic effect in reducing inflammation.
In the last three blogs we have explored how Cellix’s VenaFlux Solutions can help find promising therapies that impact microvascular thrombosis, endothelial dysfunction and inflammation in the fight against COVID-19 disease. We hope these newsletters have given you ideas for your research and Cellix would be honoured to provide you with the necessary tools. Please check out our website to learn more and review our latest blogs or contact us now for more details.
References
The European Society for Cardiology. ESC Guidance for the Diagnosis and Management of CV Disease during the COVID-19 Pandemic. https://www.escardio.org/Education/COVID-19-and-Cardiology/ESCCOVID-19-Guidance. (Last update: 10 June 2020)
Yeji Jesse Lee. 'COVID toes' might be the latest unusual sign that people are infected with the novel coronavirus. Business Insider, 23 April 2020.
Zhang et al. In-Hospital Use of Statins Is Associated with a Reduced Risk of Mortality among Individuals with COVID-19. Cell Metabolism 32, 176–187August 4, 2020.