PITTSBURGH, May 14 - A small, external bioreactor holding human cells pumped out an anti-inflammatory protein to prevent organ damage and other complications in a rat with acute inflammation caused by bacterial products in a model of sepsis, according to a report from researchers at the University of Pittsburgh School of Medicine and the McGowan Institute for Regenerative Medicine. The findings were published today in the inaugural issue of Disruptive Science and Technology.
Inflammation is a necessary biological response that brings cells and proteins to the site of tissue injury to contend with foreign agents, such as bacteria and the products they produce, and to begin the healing process, explained senior author Yoram Vodovotz, Ph.D., professor, Department of Surgery, and director, Center for Inflammation and Regenerative Modeling at the McGowan Institute. But sometimes, the inflammatory response escalates to create damage on its own, triggering more inflammation in a self-sustaining and dangerous cycle.
"In sepsis, for example, the inflammatory response evolves almost too quickly, but the available treatment strategies aim to prevent inflammation entirely," he said. "A better approach would be to turn down the response when it's too strong, yet still have appropriate inflammation signaling to promote tissue repair."
During inflammation, the body makes a protein called tumor necrosis factor-alpha, or TNF-α. It also makes its counterpart, soluble TNF-α receptor, or sTNFR, which binds to and reduces the level of TNF-α. In some situations, such as sepsis, not enough sTNFR is made to limit the inflammatory response.
Dr. Vodovotz and his team loaded a small bioreactor with human liver cells engineered to make sTNFR continuously. Through an intravenous line, blood from an anesthetized rat experiencing acute but transient inflammation was pumped through the bioreactor, exposing it to the engineered cells.
When the bioreactor was loaded with sTNFR-producing cells, sTNFR levels rose beyond what the animal could produce on its own, while TNF-α levels dropped, as did other markers of inflammation. The animal's blood pressure also improved, and markers of organ damage were reduced.
"This bio-hybrid device acts as a kind of inflammation thermostat," Dr. Vodovotz said. "By loading it with cells that produce different amounts of sTNFR, or other inflammatory blockers, we may soon be able to tailor our interventions to carefully balance inflammation and immune responses based on the patient's medical situation."
His team now is exploring the effectiveness of cells engineered to produce sTNFR based on the individual production of TNF-α, rather than continuously, in order to create a disease-specific response for each patient. Such a personalized medicine therapy platform could be extended based on emerging knowledge regarding the biology of inflammation.
The Vodovotz group also is creating computer models of inflammation, which could be used to engineer the next generation of this device. The portability of the device could be particularly useful on the battlefield, where early intervention to control systemic inflammation after injury might improve the chances of survival.
Co-authors of the paper include Rami A. Namas, M.D., Maxim Mikheev, M.D., Ph.D., Jinling Yin, M.D., Patrick Over, B.S., Matthew Young, B.S., Gregory M. Constantine, Ph.D., Ruben Zamora, Ph.D., Jörg Gerlach, M.D., Ph.D., all from the University of Pittsburgh and the McGowan Institute.
The project was funded by the U.S. Department of Defense, National Institutes of Health grant P50-GM-53789, and the Commonwealth of Pennsylvania.
About the University of Pittsburgh School of Medicine
As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1997. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.
Likewise, the School of Medicine is equally committed to advancing the quality and strength of its medical and graduate education programs, for which it is recognized as an innovative leader, and to training highly skilled, compassionate clinicians and creative scientists well-equipped to engage in world-class research. The School of Medicine is the academic partner of UPMC, which has collaborated with the University to raise the standard of medical excellence in Pittsburgh and to position health care as a driving force behind the region's economy. For more information about the School of Medicine, see www.medschool.pitt.edu.
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