University of California – UC Newsroom | Discovery could improve liver transplant success

Discovery could improve liver transplant success Email this article Date: 2013-08-01 Contact: Kathy Keatley Garvey Phone: (530) 754-6894 Email: kegarvey@ucdavis.edu

DAVIS — Researchers from multiple institutions, including the University of California, Davis and Harvard Medical School, have discovered a novel and natural means that could increase the success of human liver transplants and speed the recovery of both the patient and the donor. The study is especially significant because of the desperate shortage of livers among thousands of very ill patients, said lead researcher Dipak Panigrahy of Harvard Medical School, in work published online in the July 29th edition of Proceedings of the National Academy of Sciences (PNAS).

According to the American Liver Foundation website, 1,848 patients died in 2005 while waiting for a donated liver to become available. “Currently, about 17,000 adults and children have been medically approved for liver transplants and are waiting for donated livers to become available. The waiting list grows every year.”

The researchers found that a natural substance in blood vessels stimulates organ and tissue regeneration.

“The endothelium of blood vessels generate the lipid mediators called epoxyeicosatrienoic acids or EETs,” explained Panigrahy, assistant professor of pathology at Harvard Medical School and the Center of Vascular Biology Research at the Beth Israel Deaconess Medical Center, Boston. “EETs stimulate blood vessel formation, and organ regeneration is dependent on blood vessel formation. However, the role of EETs in organ regeneration is unknown. Our research shows that EETs stimulate organ and tissue regeneration.”

The 28-member discovered that “systemic administration of EETs significantly increased liver and lung regeneration by 23 percent to 46 percent when compared to control mice post partial liver resection,” Panigrahy said.

“This can be very useful in transplant both for the donor and the recipient in getting full function back with liver transplant,” said researcher and co-author Bruce Hammock, a distinguished professor of entomology with a joint appointment at the UC Davis Comprehensive Cancer Center.

In addition to liver transplants, “the research could lead to the success of other organ transplants and speed the recovery of both the patient and the donor,” Hammock said. It could also be a boon for other wound-healing procedures “where tissue repair and growth are crucial.”

“We are planning to evaluate EETs and soluble epoxide hydrolase (sEH) inhibitors in humans who need tissue regeneration such as organ regeneration and wound healing,” Panigrahy said. “We are working to evaluate soluble epoxide hydrolase inhibitors in humans by surgeons.” The surgeons include Mark Puder, Boston Children’s Hospital, lung regeneration; and Roger Jenkins of the Lahey Clinic, Boston, who performed New England’s first successful liver transplant in July 1983. In addition, they plan to work with other clinicians for testing EETs in stimulating wound healing in diabetic and nondiabetic patients.

Other key members of the team are Mark Kieran, Dana-Farber Cancer Institute, Boston; Mark Puder of the Boston Children’s Hospital; and Darryl C. Zeldin of the National Institute of Health’s National Institute of Environmental Sciences (NIH-NIEHS).

Panigrahy, noting the chronic shortage of livers for transplant, said that liver surgeons “urgently need novel ways to regenerate livers. With Bruce (Hammock) we are working with Dr. Roger Jenkins, who performed New England’s first successful liver transplant in July 1983.”

The research, titled “Epoxyeicosanoids Promote Organ and Tissue Regeneration” and accomplished with animal models, showed acceleration of liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Vascularization deals with blood vessel formation in abnormal tissue or in abnormal positions.

“There is a soluble epoxide hydrolase with investigational new drug status with the FDA that stabilizes these natural regulators and we could use them for compassionate trials in this area,” Hammock said. “One possible trial, with Mark Puder at Harvard, is for correcting a condition that blocks growth of lungs in newborns. We have a chance to dramatically increase the number of these babies that survive.”

“We are working on this fatal disease of newborns termed diaphramic hernia,” added Panigrahy. “So far this is all in experimental animals but we are planning to test if increasing EETs can be successful in encouraging poorly developed lungs of newborns to grow.”

In their abstract, they wrote: “…we hypothesize that endothelial cells stimulate organ and tissue regeneration via production of bioactive EETs. To determine whether endothelial-derived EETs affect physiologic tissue growth in vivo, we used genetic and pharmacological tools to manipulate endogenous EET levels. We show that endothelial-derived EETs play a critical role in accelerating tissue growth in vivo, including liver regeneration, kidney compensatory growth, lung compensatory growth, wound healing, corneal neovascularization, and retinal vascularization. Administration of synthetic EETs recapitulated these results, whereas lowering EET levels, either genetically or pharmacologically, delayed tissue regeneration, demonstrating that pharmacological modulation of EETs can affect normal organ and tissue growth. We also show that soluble epoxide hydrolase inhibitors, which elevate endogenous EET levels, promote liver and lung regeneration. Thus, our observations indicate a central role for EETs in organ and tissue regeneration and their contribution to tissue homeostasis.

Among the co-researchers are Jun Yang and Bora Inceoglu of the Hammock lab.

“We are very excited about these findings,” Inceoglu said. “Traditionally wound repair and healing is an area where we clearly lack efficacious drugs. This work demonstrates that there are natural processes one can augment and promote to accelerate wound healing. This is a hopeful moment for many patients suffering from serious conditions that can be helped with these new drugs.”

“The finding here implies the modulation of EETs in vivo might help wound healing especially for the organ transplant patients,” said Yang. “In the study, the result based on liver transplant patients supports this argument, which is very exciting and provides the basis for the translation to the clinic.”

“We are very excited about these findings,” Yang added. “Traditionally wound repair and healing is an area where we clearly lack efficacious drugs. This work demonstrates that there are natural processes one can augment and promote to accelerate wound healing. This is a hopeful moment for many patients suffering from serious conditions that can be helped with these new drugs.”

Hammock, who directs the NIEHS Superfund Research Program on the UC Davis campus, received financial support from Superfund Program and from NIH grants. He also receives financial backing as a George and Judy Marcus Senior Fellow of the American Asthma Foundation.

Other funding sources supporting the 28-member team were the National Cancer Institute Grant, the Stop and Shop Pediatric Brain Tumor Fund, the C. J. Buckley Pediatric Brain Tumor Fund, the Joshua Ryan Rappaport Fellowship, the Children’s Hospital Boston Surgical Foundation and the Vascular Biology Program, a Howard Hughes Medical Institute Research Fellowship, and the Intramural Research Program of NIH.

Panigrahy cautioned that the work is a work in progress. “Further studies are needed to carefully evaluate the benefits as well as the risks in the clinical modulation of these lipid mediators,” said Panigrahy. “EETs are a substance that can potentially link wound healing and cancer. Stimulating of EETs promotes wound healing. We have shown the ability of EET antagonists to inhibit tumor growth and metastasis. These results could pave the way for a new strategy for the prevention and treatment of metastatic disease – that is, inhibition of EET bioactivity. Specific EET antagonists, inhibitors of endothelial CYP epoxygenases, or the overexpression of EET-metabolizing enzymes may represent new strategies for the treatment of angiogenic diseases, including cancer.”

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