Ischemia Reperfusion Injury: from the lab to the clinic

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Maik Hüttemann, Ph.D., Professor of Molecular Medicine and Genetics and Biochemistry, Microbiology, and Immunology at the WSU Center for Molecular Medicine and Genetics. 

A new study to gauge the effectiveness of infrared light therapy in preventing ischemia-reperfusion injury is getting underway under the direction of Dr. Maik Hüttemann (Professor of Molecular Medicine and Genetics and of Biochemistry, Microbiology, and Immunology). The study is based on previous basic research by Hüttemann showing that the damage caused after relieving a blood flow interruption such as is found in ischemic stroke or cardiac arrest is produced by the hyperactivity of the terminal enzyme of the electron transport chain, cytochrome c oxidase (COX), which promotes damaging free radical species (ROS), and that there are wavelengths of infrared light that can reduce COX activity and thereby protect against this ROS damage.

Paradoxically, as oxygen delivery is restored, mitochondria become hyperactive, and thus ROS production increases exponentially, causing cellular dysfunction and death. For example, during a stroke, when a blood clot prevents oxygen from entering brain tissue, the only way to restore oxygen delivery and save the tissue is to remove the blood clot. "What wasn't understood for so long," Hüttemann says, "is that when you open up the blood vessel to do this [remove the blood clot], it creates additional damage in the form of reperfusion damage."

Hüttemann studies mitochondrial regulation under stress, specifically the regulation of cytochrome c oxidase and cytochrome c, which are key components in mitochondrial oxidative phosphorylation—Mitochondria function to produce the energy used to power all processes in the body. ROS, also called free radicals, are a byproduct of this energy production process, and the overproduction of ROS is implicated in cell dysfunction and death. COX is found to be key in the absorption of infrared light, which affects the regulation of mitochondrial function and ROS production.

Hüttemann started working on noninvasively preventing ischemia-reperfusion injury through the usage of infrared light in 2006 when he received an initial grant from the Wilson Foundation. With this grant, he and his collaborators identified wavelengths of infrared light (750 nm and 950 nm) that inhibit mitochondrial function. Hüttemann explains that "typically, other literature has focused on and shown that infrared light activates mitochondrial function at wavelengths of 810 nm." Their discovery identified wavelengths of infrared light with an inhibitory effect on mitochondrial function.

Building on these findings, Hüttemann and Dr. Thomas Sanderson (Associate Professor of Emergency Medicine and Molecular & Integrative Physiology, University of Michigan) developed the technology to apply inhibitory wavelengths of infrared light to ischemic tissue during reperfusion to prevent injury. Small and large animal testing has been successfully conducted on rats and pigs. The work was so encouraging that Hüttemann and Sanderson founded a startup company, Mitovation, to advance this technology. The success of the large animal work with pigs led them to apply for an NIH U44 grant to carry out a clinical trial. This $6.5 million grant was just awarded, and with it, Hüttemann is building a medical device emitting infrared light for a trial at the Children's Hospital of Michigan. The device will distribute infrared light over a large, controlled area to ensure the patient's safety.

Hüttemann credits this project's success and progress to his team's persistence and the support he has received over the years. He would like to recognize the efforts and contributions of his colleagues and collaborators, particularly Sanderson, Dennis Goebel, Moh Malek, and Kathleen Meert, and their lab members. "From the initial grant awarded by the Wilson Foundation to the continued institutional support provided by WSU, this technology has received a great deal of support," says Hüttemann, noting that he and his collaborators are "incredibly motivated in making a difference for patients."