- Author: Kathy Keatley Garvey
Researchers from Harvard Medical School and the University of California, Davis, blocked the progression of cancer growth caused by environmental carcinogens and food contaminants by resolving an eicosanoid/cytokine storm triggered by cell debris.
The research, from the laboratories of physician-researcher Dipak Panigrahy of Harvard Medical School and UC Davis distinguished professor Bruce Hammock, is published in the current edition of the Proceedings of the National Academy of Sciences.
“We advanced the hypothesis that cell debris from chemotherapy, resection of tumors and even immunotherapy can make these therapies a double-edged sword stimulating cancer growth and metastasis while treating it,” said Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center.
In their paper, “Resolution of Eicosanoid/Cytokine Storm Prevents Carcinogen and Inflammation-Initiated Hepatocellular Cancer Progression,” the scientists covered the potent environmental carcinogen and food contaminant aflatoxin. Aflatoxins are toxins produced by certain fungi that are found in such agricultural crops as corn, peanuts, cottonseed, and nuts.
“Not only is this fungal metabolite genotoxic but it is also a tumor promoter,” said Hammock, defining a genotoxic agent as “a chemical that damages cellular DNA, resulting in mutations or cancer.”
Lead authors Anna Fishbein of Harvard University, a recently enrolled medical student in the Georgetown University School of Medicine, and Weicang Wang, a postdoctoral scholar in the Hammock lab, said aflatoxin exerts some of its cancer-promoting effects by generating cell debris which activate a pathway leading to eicosanoid and cytokine storms. These two classes of natural chemical mediators, they explained, control many of our defenses against pathogens, but when out of control, these storms lead to growth and metastasis of liver cancer.
“We demonstrated that debris generated by aflatoxin B1accelerates tumor dormancy escape in liver cancer models by stimulating a macrophage-derived eicosanoid and cytokine storm of pro-inflammatory mediators,” said Fishbein. “Thus, targeting a single inflammatory mediator or eicosanoid pathway is unlikely to prevent carcinogen-induced tumor progression.”
The researchers showed that the inhibition of the soluble epoxide hydrolase (sEH) pathway or the combined inhibition sEH and cyclooxygenase-2 (COX-2) pathways prevented the carcinogen debris-induced storm of both cytokines and lipid mediators by macrophages--specialized detect-and-destroy cells.
In animal models, the dual COX-2/sEH inhibitor PTUPB prevented the onset of debris-stimulated liver cancer. The dual inhibition of COX-2/sEH pathways may be “a novel approach” to control cancer of the liver, the researchers said.
“We also showed that carcinogen-generated debris stimulates an endoplasmic reticulum (ER) stress response which may promote HCC progression. Importantly, PTUPB prevents the ER stress response,” Wang added. “We created a novel model of debris-stimulated liver cancer designed to study new strategies for the prevention and treatment of carcinogen-induced cancers with tremendous potential to translate to the clinic.”
From a nutritional standpoint, aflatoxin is a common food contaminant, Wang said. “But good agricultural practice and post-harvest technology keep the levels very low. However, in much of the world, aflatoxin levels are so high that many crops are discarded. In other cases, these contaminated grain and nut crops enter the human food chain, where they cause acute toxicity, severe anemia and of course later lead to cancer.”
UC Davis co-author and nutritional scientist Yuxin Wang (who is the wife of Weicang Wang) said that “finding a way to modulate the events that lead to the eicosanoid storm would have a major effect on children's health in many developing countries.”
Fishbein and Allison Gartung of the Panigrahy lab not only used the soluble epoxide hydrolase inhibitors from the Hammock lab but also used some prototype drugs synthesized by chemist Sung Hee Hwang of the UC Davis School of Veterinary Medicine “which proved to be even better,” Hammock said.
“These compounds are a synthetic combination of cyclooxygenase inhibitors like celebrex with epoxide hydrolase inhibitors,” Hammock said. “Since epoxide hydrolase inhibitors stabilize the endoplasmic reticulium stress response and transcriptionally down regulate inflammatory cyclooxygenase we expected them to synergize with cyclooxygenase inhibitors. We were surprised and pleased with the dramatic interaction of these inhibitors when combined in the same molecule in reducing the cytokine and eicosanoid production by in response to cell debris.”
“The observations from Harvard show that by inhibiting soluble epoxide hydrolase, we can block the activation of these inflammatory cascades leading to tumor promotion, growth and metastasis,” Hammock said. “We have a compound in human clinical trials that inhibits sEH, which should be clinically available in a few years. In addition. we have found natural inhibitors of the epoxide hydrolase in a variety of plants, including crop plants. This may allow us to reduce the cancer risk and block the gastrointestional erosion and bleeding caused by dietary aflatoxin using natural means.”
Other members of the 15-member team are UC Davis researchers Jun Yang, Yuxin Wang and Sung Hee Hwang; Harvard researchers Haixia Yang, Victoria Hallisey, Jianjun Deng, Sanne Verheul, Allison Gartung, Diane Bielenberg and Mark Kiernan (now of Bristol-Myers Squibb); and Sui Huang, Institute for Systems Biology, Seattle. Hammock and Panigrahy are the corresponding authors.
The research drew strong financial support as the Panigrahy's laboratory is generously supported by the Credit Unions Kids at Heart Team, the CJ Buckley Pediatric Brain Tumor Fund, and the Joe Andruzzi Foundation; and Hammock's UC Davis grants from the National Institute of Environmental Health (NIEHS) Superfund Research Program, and the NIEHS RIVER Award (Revolutionizing Innovative, Visionary, Environmental Health Research).
Hammock, a member of the UC Davis faculty since 1980, has directed the UC Davis Superfund Research Program for nearly four decades. It supports scores of pre- and postdoctoral scholars in interdisciplinary research in five different colleges and graduate groups on campus. Last year Hammock received a $6 million, eight-year “Outstanding Investigator” federal grant for his innovative and visionary environmental health research: The award is part of the Revolutionizing Innovative, Visionary Environmental Health Research (RIVER) Program of NIEHS.
The abstract:
“Toxic environmental carcinogens promote cancer via genotoxic and nongenotoxic pathways, but nongenetic mechanisms remain poorly characterized. Carcinogen-induced apoptosis may trigger escape from dormancy of microtumors by interfering with inflammation resolution and triggering an endoplasmic reticulum (ER) stress response. While eicosanoid and cytokine storms are well-characterized in infection and inflammation, they are poorly characterized in cancer. Here, we demonstrate that carcinogens, such as aflatoxin B1 (AFB1), induce apoptotic cell death and the resulting cell debris stimulates hepatocellular carcinoma (HCC) tumor growth via an ‘eicosanoid and cytokine storm.' AFB1-generated debris up-regulates cyclooxygenase-2 (COX-2), soluble epoxide hydrolase (sEH), ER stress-response genes including BiP, CHOP, and PDI in macrophages. Thus, selective cytokine or eicosanoid blockade is unlikely to prevent carcinogen-induced cancer progression. Pharmacological abrogation of both the COX-2 and sEH pathways by PTUPB prevented the debris-stimulated eicosanoid and cyto- kine storm, down-regulated ER stress genes, and promoted macrophage phagocytosis of debris, resulting in suppression of HCC tumor growth. Thus, inflammation resolution via dual COX-2/sEH inhibition is an approach to prevent carcinogen-induced cancer.”
- Author: Kathy Keatley Garvey
As of July 8, the commentary, “Inflammation Resolution: a Dual-Pronged Approach to Averting Cytokine Storms in COVID-19?”—the work of a nine-member team of Harvard University and UC Davis researchers—has been downloaded 11,444 times since its publication May 8, 2020. It is online at https://rdcu.be/b33IN.
In comparison, the most downloaded publication in CMR in 2019 received 5,712, statistics show.
Editor-in-Chief and Professor Kenneth Honn, who selected their commentary as the top paper of the month, said it drew more downloads the first week of publication than any other in the journal's history. 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.
“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 pro-resolution 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.”
The drug is an inhibitor to the soluble epoxide hydrolase (sEH) enzyme, a key regulatory enzyme involved in the metabolism of fatty acids.
Panigraphy and Hammock said they are receiving “tons of calls, media requests and emails” from all over the world, including Norway, Japan, United Kingdom, Germany, France, Mexico and Belgium.
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 as well as eicosanoids.
“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.
The co-authors include two physician-researchers: 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).
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.
National Institutes of Health (NIH) grants, including a National Institute of Environmental Health Science (River Award) to Hammock, helped fund the research. 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.
- Author: Kathy Keatley Garvey
The annual campuswide award honors researchers who have made a long-term positive impact on the lives of others and who inspire other innovators. It is one of several awards announced June 15 in a program managed by the Office of Research. (See recipients.)
“Research universities like UC Davis play a critical role in advancing innovative solutions for the global community that not only stimulate our economy but create a better quality of life,” said Chancellor Gary S. May in a news release. “The recipients of this year's awards demonstrate the impact of reaching beyond what is expected to deliver game-changing innovations that address some of the world's most critical issues.”
Hammock, who holds a joint appointment with the Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, co-discovered a human enzyme termed Soluble Epoxide Hydrolase (sEH), a key regulatory enzyme involved in the metabolism of fatty acids. It regulates a new class of natural chemical mediators, which in turn regulates inflammation, blood pressure and pain. Hammock and his lab have been involved in enzyme research for more than 50 years.
Hammock is the founder and chief executive officer of the Davis-based pharmaceutical company, EicOsis LLC, formed in 2011 to develop an orally active non-addictive drug for inflammatory and neuropathic pain for humans, as well as a version in development for treating painful conditions in companion animals. A drug candidate known as EC5026 and now in human trials, targets a novel pathway to block the underlying cause of certain types of pain.
UC Davis recently licensed certain patents exclusively to EicOsis that support the underlying technology.
“My research led to the discovery that many regulatory molecules are controlled as much by degradation and biosynthesis,” Hammock said. “The epoxy fatty acids control blood pressure, fibrosis, immunity, tissue growth, depression, pain and inflammation to name a few processes.”
The National Institute on Drug Abuse awarded a $15 million HEAL grant (Helping to End Addiction Long-term Initiative) to EicOsis in 2019 to support human clinical trials of a novel compound that has been found effective for the treatment of pain in preclinical animal studies.
In 2019, Hammock received a $6 million “outstanding investigator” federal grant for his innovative and visionary environmental health research. His pioneering work on inflammation not only extends to alleviating chronic pain, but to targeting inflammation involved in cancer, cardiovascular diseases, diabetes and other health issues.
EicOsis won the Sacramento Region Innovation Award in the Medical and Health category in 2019.
More recently, Hammock has turned his attention to using sEH as a means to control the deadly cytokine storm associated with COVID-19.
A member of the UC Davis faculty since 1980, Hammock has directed the UC Davis Superfund Research Program (funded by the National Institutes of Health's National Institute of Environmental Health Sciences) for nearly four decades, supporting scores of pre- and postdoctoral scholars in interdisciplinary research in 5 different colleges and graduate groups on campus. He is a fellow of the National Academy of Inventors and the National Academy of Sciences, and the Entomological Society of America. He is the recipient of scores of awards, including the first McGiff Memorial Awardee in Lipid Biochemistry; and the Bernard B. Brodie Award in Drug Metabolism, sponsored by the America Society for Pharmacology and Experimental Therapeutics. At UC Davis he received the Distinguished Teaching Award and the Faculty Research Lectureship.
He has authored or co-authored more than 1,200 peer-reviewed publications and holds more than 95 patents in agriculture, environmental science and medicinal chemistry.
Hammock is known for his expertise in chemistry, toxicology, biochemistry and entomology. Early in his career, he founded the field of environmental immunoassay, using antibodies and biosensors to monitor food and environmental safety, and human exposure to pesticides. His groundbreaking research in insect physiology, toxicology led to his development of the first recombinant virus for insect control.
As director of the UC Davis Superfund Research Program, he pioneered trans-disciplinary research across campus, engaging faculty in multiple colleges and schools “to transform the way we treat diseases in multiple species.”
A native of Little Rock, Ark., Hammock received his bachelor's degree in entomology (with minors in zoology and chemistry) magna cum laude from Louisiana State University, Baton Rouge, in 1969. He received his doctorate in entomology-toxicology from UC Berkeley in 1973. Hammock served as a public health medical officer with the U.S. Army Academy of Health Science, San Antonio, and as a postdoctoral fellow at the Rockefeller Foundation, Department of Biology, Northwestern University, Evanston, Ill.
In the Army, he served as a medical officer at Fort Sam, Houston, and what he saw--severely burned people in terrible pain--made a lasting impression on him and steered him toward helping humankind.
Links:
- Author: Kathy Keatley Garvey
ASD, which impacts the nervous system, affects 1 percent of the U.S. population or 62.2 million globally. An estimated 64 percent and 91 percent of the population are at risk genetically.
The researchers' latest paper, “Maternal Glyphosate Exposure Causes Autism-Like Behaviors in Offspring through Increased Expression of Soluble Epoxide Hydrolase,” appears in the current edition of the Proceedings of the National Academy of Sciences (PNAS). Glyphosate is a broad-spectrum systemic herbicide and crop desiccant used to kill broadleaf weeds and grasses that compete with agricultural crops.
“In the research of autism, brain-gut-microbiota axis plays a key role in ASD from human studies,” said lead researcher and neurobiologist Kenji Hashimoto of the Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan. “Accumulating evidence suggests abnormal composition of gut microbiota in subjects with autism. In this study, we found abnormal composition of gut microbiota in offspring after maternal glyphosate exposure. Thus, exposure of glyphosate during pregnancy may cause abnormal composition of gut microbiota in offspring, resulting in the risk for autism.'
The drug discovered in the Hammock lab inhibits sEH, a natural enzyme that regulates epoxy fatty acids, “which control blood pressure, fibrosis, immunity, tissue growth, depression, pain and inflammation to name a few processes,” said co-author Hammock, a distinguished professor with a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. Human clinical trials underway to see if the non-addictive drug relieves chronic pain.
“It is critical to appreciate that mouse models are not absolutely predictive of the human situation,” Hammock said.“Similarly, maternal immune stress is simply a model that gives behavioral changes in the offspring. That said, it is a relevant model of abnormalities in mental development in the offspring. This is a widely used model of the effect of maternal stress on the next generation that has been established in many species, including nonhuman primates. Sadly, maternal stress was shown tightly associated with the mental state of human children as well.”
“Such studies are important to generate hypotheses of environmental risk,” said Hammock, who meshes his expertise in chemistry, toxicology, biochemistry and entomology, in his 50-year research to find a non-addictive drug to control chronic pain. “Because we only saw maternal immune stress at exceptionally high doses of glyphosate, our data fail to support the hypothesis that glyphosate exposure causes autism with expected dietary, environmental or even occupational exposure.”
The research drew financial support from the Japan Society for the Promotion of Science (to Hashimoto); and the National Institute of Environmental Health Sciences (NIEHS) River Award (to Hammock), and NIEHS Superfund Program (to Hammock). Hammock has directed the UC Davis Superfund Program for nearly four decades.
The Hashimoto-directed Chiba group has shown that these drug candidates prevent and even reverse a variety of chronic diseases of the central nervous system in mice and human cells including ASD like behaviors.
The 16 co-authors include Hammock lab researchers Jun Yang, Sung Hee Hwang and Debin Wan.
Yang said that the researchers “hypothesized that the role of the sEH is important in the pathogenesis of ASD in offspring after maternal glyphosate exposure based on our previous finding that sEH plays a key role in the development of ASD-like behavioral abnormalities in juvenile offspring after maternal immune activation (MIA), a prenatal environmental factor.”
Said Hwang: “Some epidemiological studies suggest an association between glyphosate use in agriculture and increases in autism like disorders. The doses we used in mice were so high that we fail to support glyphosate epidemiological associations between the herbicide use and the cause ASD-like behaviors.
The PNAS abstract:
“Epidemiological studies suggest that exposure to herbicides during pregnancy might increase risk for autism spectrum disorder (ASD) in offspring. However, the mechanisms underlying the risk of ASD by herbicides such as glyphosate remain unclear. Soluble epoxide hydrolase (sEH) in the metabolism of polyunsaturated fatty acids is shown to play a key role in the development of ASD in offspring after maternal immune activation. Here, we found ASD-like behavioral abnormalities in juvenile offspring after maternal exposure to high levels of formulated glyphosate.
“Furthermore, we found increases in sEH in the prefrontal cortex (PFC), hippocampus, and striatum of juvenile offspring and oxylipin analysis showed decreased levels of epoxy-fatty acids such as 8(9)-EpETrE in the blood, PFC, hippocampus, and striatum of offspring after maternal glyphosate exposure, supporting increased activity of sEH in the offspring. Moreover, we report abnormal composition of gut microbiota and short chain fatty acids in fecal samples of juvenile offspring after maternal glyphosate exposure. Interestingly, oral administration of TPPU (an sEH inhibitor) to pregnant mothers from E5 to P21 prevented ASD-like behaviors such as social interaction deficits and increased grooming time in the juvenile offspring. These findings suggest that maternal exposure to high levels of glyphosate causes ASD-like behavioral abnormalities and abnormal composition of gut microbiota in juvenile offspring, and that increased activity of sEH might play a role in ASD-like behaviors in offspring after maternal glyphosate exposure. Therefore, sEH may represent a target for ASD in offspring after maternal stress from occupational exposure to contaminants.
“Maternal exposure to high levels of the herbicide glyphosate may increase the risk for autism spectrum disorder (ASD) in offspring; however, the underlying mechanisms remain largely unknown. Maternal glyphosate exposure during pregnancy and lactation caused ASD-like behavioral abnormalities and abnormal composition of gut microbiota in murine male offspring. Soluble epoxide hydrolase (sEH) in the brain of offspring after maternal glyphosate exposure was higher than controls. Treatment with an sEH inhibitor from pregnancy to weaning prevented the onset of ASD-like behavioral abnormalities in offspring after maternal glyphosate exposure. The glyphosate exposures used here exceed any reasonable dietary, environmental or occupational exposure, but they indicate that increased sEH plays a role in ASD-like behaviors in offspring.”
- Author: Kathy Keatley Garvey
(See commentary published in journal Cancer Metastasic and Reviews at https://rdcu.be/b33IN)
A drug discovered in the laboratories of Professors Charles Serhan of Harvard Medical School and Bruce Hammock of 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.
“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 pro-resolution 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.
“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.
“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 diabetic-hypertensive 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 another EicOsis 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 thesis of former doctoral 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.
Severe coronavirus disease (COVID-19) is characterized by pulmonary hyper-inflammation 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 acid-derived epoxyeicosatrienoic acids (EETs), which also stimulate inflammation resolution by promoting the production of pro-resolution mediators, activating anti-inflammatory 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.
