- 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
Earlier research by the Judah Folkman laboratory of Harvard Medical School showed that cutting off blood vessels that feed a cancerous tumor can stop its growth.
The seven-member research team—five from the Bruce Hammock laboratory of UC Davis—“characterized a novel lipid signaling molecule that can change fundamental biological processes involved in our health and disease,” said lead author and researcher Amy Rand. “We've found that a novel product derived from the metabolism of omega-6 fatty acids stimulates angiogenesis, which may contribute to enhanced tumor growth by providing tumors with oxygen and nutrients.”
“As a highly regulated process, angiogenesis is critical for wound healing and development, but many diseases result in unregulated angiogenesis, including cancer,” explained Rand, a postdoctoral fellow in the lab of Bruce Hammock, a distinguished professor who holds a joint appointment with UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center. “We may be able to control angiogenesis to stimulate wound healing when necessary, but also block tumor growth in patients. Diseases that rely on angiogenesis may be able to be treated in part by changes in dietary lipid exposure or by controlling levels of these metabolites through enzyme inhibitors that block their formation.”
The research, published April 10 in the Proceedings of the Natural Academy of Sciences (PNAS), explains, in part, why inhibiting the soluble epoxide hydrolase (sEH) in some systems is angiogenic whereas combining sEH inhibition with the inhibition of cyclooxygenase (COX) enzymes is dramatically antiangiogenic, which in turn may suppress tumor growth.
“There's uncertainty regarding the link between unsaturated fats and cancer, due to ongoing conflicts between scientific studies and insufficient data,” Rand said. “Because of this, there is a major gap in our understanding of how these essential dietary fats affect our health. We used tools to detect and characterize unknown metabolites from omega-6 unsaturated fats and determined their effect on angiogenesis, to address at least a small part of this uncertainty by focusing on how these fats contribute to cancer tumor growth.”
Hammock, who holds a joint appointment in the UC Davis Department of Entomology and Nematology and the UC Davis Comprehensive Cancer Center, said the research, titled “Cyclooxygenase-Derived Proangiogenic Metabolites of Epoxyeicosatrienoic Acids
Holds long term hope for cancer patients and those afflicted with heart, eye and other diseases. The team also included Christophe Morisseau, Bogdan Barnych, and Kin Sing Stephen Lee all of the UC Davis Department of Entomology and Nematology and UC Davis Comprehensive Cancer Center; Tomas Cajka of the UC Davis Genome Center; and Dipak Panigraphy of Harvard Medical School. Lee is now an assistant professor at Michigan State University.
“Pro and anti-angiogenic therapy can potentially help millions of people worldwide in various diseases such as heart, ulcers, eye and cancer as first demonstrated by Dr. Judah Folkman and his colleagues,” said Panigraphy, formerly of the Hammock lab and now with the Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, and the school's Department of Pathology.
“While the COX and sEH pathways can be targeted with drugs, their interaction is poorly understood,” Panigraphy said. “These studies by Rand et al demonstrate for the first time new specific mechanisms whereby targeting the sEH pathway can be both pro- and anti-angiogenic and has the potential to help patients with devastating diseases such as in the eye and cancer where blocking angiogenesis is desired.”
Rand, who received her doctorate in chemistry from the University of Toronto, Canada, in 2013, the same year she joined Hammock's biological analytical chemistry lab, said she's “always been interested in research that combines chemistry and biology to enhance our understanding of human health.”
Future work? “We aim to understand the direct involvement of these omega-6 fatty acid metabolites with cancer tumor growth and metastasis.”
Rand last year received the $100,000 Judah Folkman Fellowship for Angiogenesis Research from the American Association for Cancer Research. She won the highly competitive international award for her proposal, “Regulation of Cancer Angiogenesis from the Metabolism of Epoxy Omega-6 Fats.” Rand joined Hammock's biological analytical chemistry lab in 2013 and was a fellow on the Oncogenic Signals and Chromosome Biology T32 Training Grant, UC Davis Department of Microbiology and Molecular Genetics.
The late Judah Folkman (1933-2008), a Harvard Medical School professor considered the father of angiogenesis research, “is best known for pioneering the concept of blocking angiogenesis (the development of blood vessels) to control cancer growth," Hammock said. "This concept has resulted in a number of anti-cancer drugs and has had a major impact on cancer treatment. Of course, blood vessel development is also critical for survival."
Folkman discovered that cutting off the blood vessels that feed the tumor can stop cancer tumor growth. His revolutionary work has led to the discovery of a number of therapies based on inhibiting or stimulating neovascularization. Inhibitors of the sEH pathway are moving toward human trials to control neuropathic pain, but if combined with nonsteroidal anti-inflammatory drugs can block tumor growth by blocking angiogenesis. So Dr. Sung Hee Hwang combined inhibitors of both pathways into one molecule which is being investigated in cancer models at the UC Davis Cancer Center by Dr. Paul Henderson and Northwestern University Medical School by Dr. Guang-yu Yang.
Hammock directs the campuswide Superfund Research Program, National Institutes of Health Biotechnology Training Program, and the National Institute of Environmental Health Sciences (NIEHS) Combined Analytical Laboratory.
This work was supported by NIEHS and the NIEHS Superfund Program; and two of Rand's grants: the Oncogenic Signals and Chromosome Biology T32 Training Grant, NIH/NIEHS; and her 2016 AACR Judah Folkman Fellowship for Angiogenesis Research.