The National Institute of Environmental Health Sciences has awarded a five-year, $1.7 million grant to Serrine Lau, a professor at the University of Arizona College of Pharmacy, to study how all-Trans Retinoic Acid, or ATRA, a metabolite of Vitamin A, reduces organ damage caused by the sudden reintroduction of oxygen to cells and organs.
Lau, who directs the college's Southwest Environmental Health Sciences Center, led a team that discovered that ATRA protects against cell damage caused by oxidative stress, a shortage of the blood supply to an organ.
Oxidative stress occurs after ischemia, a condition in which blood supply to an organ has been reduced or cut off. If blood suddenly is re-introduced to an ischemic organ, the abrupt increase in oxygen can kill cells and, subsequently, the organ. This damage is known as ischemic-reperfusion injury.
"When blood supply to an organ is reduced or cut off, such as during a transplant operation," Lau said, "the organ adjusts to less oxygen. This also happens naturally as people age, as their arteries become more occluded – narrower – and less oxygen flows through them. The organs being fed by those arteries adjust to having less oxygen. However, when oxygen is suddenly reintroduced, such as when clamped arteries are released after a transplant operation or when a person undergoes artery-opening surgery, cell death and organ death can occur. Too much oxygen is not necessarily a good thing."
Lau's team discovered that pretreating animals with ATRA completely abolished the toxicity caused by reintroducing oxygen to cells and organs that had adjusted to a lower supply, such as in the case of ischemic-reperfusion injury. The team also learned that ATRA is best administered three to six hours prior to the onset of ischemia, and that only a tiny dose is necessary for the beneficial effect: 1 milligram per kilogram of body weight.
"This discovery is very exciting," Lau said. "Megadoses of ATRA are known to cause birth defects – but we don't have to give megadoses. We can give very small doses and realize the full protective effect of this vitamin A metabolite against the known destructive effects of oxidative stress."
Lau said treatment with ATRA could be beneficial in a range of diseases associated with ischemic conditions. For example, physicians recently reported that ATRA successfully reduced life-threatening ischemic stroke in acute promyelocytic leukemia associated with spreading coagulation.
Funding from the National Institutes of Health has enabled Arizona Health Sciences Center researchers to make great strides in understanding cancer, diabetes, heart disease, stroke, Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, osteoporosis, asthma, infectious diseases, age-related macular degeneration and many other diseases.
NIH medical research funding helps Arizonans – and all Americans – lead longer and healthier lives, and benefits Arizona's economic health as well through skilled jobs, purchasing, technology transfer, spin-off companies and the education of future health-care professionals.