A drug discovered in the Bruce Hammock laboratory at the University of California, Davis may control the body’s inflammatory response to COVID-10 and could help patients recover, according to a nine-member research team’s newly published commentary in the journal Cancer Metastasis and Reviews, Springer Nature publishing group. (See https://rdcu.be/b33IN)
“COVID-19 results in excessive inflammation and a cytokine storm caused by the human body’s reaction to the SARS-CoV-2 virus,” said lead author Dipak Panigrahy, a Harvard University physician and researcher who collaborates with the Hammock laboratory.
“Controlling the body’s inflammatory response to COVID-19 will likely be as important as anti-viral therapies or a vaccine,” Panigraphy said. “Stimulation of inflammation resolutions via proresolution lipid mediators that are currently in clinical trials for other inflammatory diseases is a novel approach to turning off the inflammation and preventing the cytokine storm caused by COVID-19.”
“We propose that this drug will alleviate the cytokine storms that occur when the immune system is overwhelmed, when the patient is battling for survival,” Panigrahy said.
The drug is an inhibitor to the soluble epoxide hydrolase (sEH) enzyme, a key regulatory enzyme involved in the metabolism of fatty acids.
Editor-in-Chief and Professor Kenneth Honn selected their commentary, “Inflammation Resolution: a Dual-Pronged Approach to Averting Cytokine Storms in COVID-19?,” as the top paper of the month. The work is based on more than 40 years of eicosanoid research from the Hammock lab and more than 40 years of eicosanoid research from the Charles Serhan lab at Harvard Medical School.
Pioneering research from the Panigrahy and Hammock labs shows that cell debris from surgery, chemotherapy, toxin exposure and other causes lead to production of high levels of pro-inflammatory mediators commonly called cytokines.
“The tremendous cell destruction caused by COVID in the lungs leads to cell debris, activating a series of events leading to the cytokine storm and mortality,” Panigrahy said. “Controlling inflammation is key to resolving any intense infection, and thus, desired treatments should modulate and particularly resolve inflammation.”
“A rapid immune response is critical to controlling this virus,” Panigrahy emphasized.
“We believe it holds promise to combat the inflammation involved with this disease,” said co-author Hammock, a UC Davis distinguished professor who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “It hit me in March that what we really need to do is not so much block cytokines as to move upstream to modulate them and resolve them rather than block inflammation.”
“We can increase the concentration of natural pro-resolving mediators termed EETs which act on a biological system to produce other pro-resolution mediators which modulate inflammation and actively resolve the process,” explained Hammock, who founded the Davis-based company EicOsis Human Health LLC, to bring the inhibitor to human clinical trials, which are underway in Texas.
Co-authors include three physician-researchers: Serhan, Patricia Sime of the Division of Pulmonary and Critical Care Medicine, Virginia Commonwealth University, Richmond, and Irene Cortés-Puch of the Division of Pulmonary, Critical Care and Sleep Medicine, UC Davis Medical Center, and an EicOsis project scientist.
“It is this resolution of inflammation and the subsequent repair that is critical to restore patient health,” said Serhan, whose studies with collaborator Sime show that immune resolution and repair are active processes in the lungs and other tissues. What drives the process, Serhan said, is the production of specific pro-resolving agents (SPMs).
Puch, who did research at the National Institutes of Health (NIH) on acute respiratory distress syndrome (ARDS) and sepsis, said the drug should be effective in treating ARDS, which she defined as “a respiratory failure characterized by rapid onset of widespread inflammation in the lungs and common among seriously ill COVID-19 patients.”
“We think there are a series of control systems that fail to modulate the patient’s response in COVID,” Cortés-Puch said. “The severe outcomes in some patients from the virus infection often are attributed to the cytokine storm, and blocking these cytokines represents a major therapeutic effort, which so far has failed. Our view is that we can move several steps upstream and control the cytokine storm not just at the level of individual cytokines and in doing so, we can encourage resolution of inflammation. In doing so, we can encourage resolution of inflammation.”
Said William Schmidt, EicOsis vice president of clinical development: “Our drug candidate has not caused any adverse effects at high doses in diabetichypertensive patients. Since this soluble epoxide hydrolase inhibitor acts upstream to down-regulate the eicosanoid and the cytokine storm, we are optimistic that it can help patients.” The Federal Drug Administration recently granted the drug candidate a “fast track” status. “In the meantime, we are looking at blood markers through time that are helping us to see the order of events leading from the original virus infection to the severe organ damage and cytokine storm that occurs in the most severe cases,” said Cindy McReynolds, a UC Davis doctoral student in pharmacology/ toxicology, and EicOsis project manager.
Hammock said the UC Davis team began researching cytokine storms 16 years ago in projects based on the student Kara Schmelzer. Now the UC Davis and Harvard scientists are targeting COVID-19.
Said Hammock: “In March, Cindy, Irene and I worked on a grant proposal with a group of scientists from the European Union to combine an anti-viral agent with an anti-inflammatory agent.”
“It hit me at that time,” Hammock reiterated, “that what we really need to do is not so much block cytokines as to move upstream to modulate them and resolve rather than block inflammation. We are lucky to have been working on such a resolving agent at UC Davis for decades.”
Other co-authors of the paper are Molly Gilligan and Allison Gartung of the Panigrahy lab; Sui Huang of the Institute for Systems Biology, Seattle; and Richard Phipps, independent scholar, Richmond, Va.
Much of the research was funded by NIH grants, including a National Institute of Environmental Health Science (River Award) to Hammock. The Panigrahy laboratory is generously supported by the Credit Unions Kids at Heart Team; the C.J. Buckley Pediatric Brain Tumor Fund; and the Joe Andruzzi Foundation.
The abstract:
Severe coronavirus disease (COVID-19) is characterized by pulmonary hyperinflammation and potentially life-threatening “cytokine storms”. Controlling the local and systemic inflammatory response in COVID- 19 may be as important as anti-viral therapies. Endogenous lipid autacoid mediators, referred to as eicosanoids, play a critical role in the induction of inflammation and pro-inflammatory cytokine production. SARS-CoV-2 may trigger a cell death (“debris”)-induced “eicosanoid storm”, including prostaglandins and leukotrienes, which in turn initiates a robust inflammatory response. A paradigm shift is emerging in our understanding of the resolution of inflammation as an active biochemical process with the discovery of novel endogenous specialized pro-resolving lipid autacoid mediators (SPMs), such as resolvins. Resolvins and other SPMs stimulate macrophage-mediated clearance of debris and counter pro-inflammatory cytokine production, a process called inflammation resolution. SPMs and their lipid precursors exhibit anti-viral activity at nanogram doses in the setting of influenza without being immunosuppressive. SPMs also promote anti-viral B cell antibodies and lymphocyte activity, highlighting their potential use in the treatment of COVID- 19. Soluble epoxide hydrolase (sEH) inhibitors stabilize arachidonic acidderived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating antiinflammatory processes, and preventing the cytokine storm. Both resolvins and EETs also attenuate pathological thrombosis and promote clot removal, which is emerging as a key pathology of COVID-19 infection. Thus, both SPMs and sEH inhibitors may promote the resolution of inflammation in COVID-19, thereby reducing acute respiratory distress syndrome (ARDS) and other life-threatening complications associated with robust viral-induced inflammation. While most COVID-19 clinical trials focus on “anti-viral” and “anti-inflammatory” strategies, stimulating inflammation resolution is a novel host-centric therapeutic avenue. Importantly, SPMs and sEH inhibitors are currently in clinical trials for other inflammatory diseases and could be rapidly translated for the management of COVID-19 via debris clearance and inflammatory cytokine suppression. Here, we discuss using pro-resolution mediators as a potential complement to current anti-viral strategies for COVID-19.
