A diverse team of immunologists, engineers and critical care clinicians at the University of Rochester Medical Center received $4 million from the National Institutes of Health to study sepsis, an over-the-top immune response to an infection that leads to organ failure and death in about one third of patients. Beyond administering antibiotics, fluids and other supportive measures, physicians have no specific treatment to stop the syndrome, which is the most expensive condition treated in U.S. hospitals, according to the Agency for Healthcare Research and Quality.
In sepsis, an army of immune cells storms the body, intending to kill the virus or bacteria causing the infection. But, the rush of immune cells is so strong that it breaks through the walls of blood vessels, creating leaks in vessels that supply blood to the lungs, kidneys, liver, intestines and heart. These organs eventually fail because they don’t get the resources they need.
The Rochester team, led by Minsoo Kim, Ph.D., associate professor of Microbiology and Immunologyat the School of Medicine and Dentistry’s David H. Smith Center for Vaccine Biology and Immunology will examine the complex chain of events that allows immune cells to penetrate vessel walls. Kim, who has studied sepsis for the past 10 years, says that understanding this process may allow scientists to control, delay or even prevent the vascular leakage that is a major contributor to death in patients with sepsis.
Anthony P. Pietropaoli, M.D., M.P.H., a critical care specialist at UR Medicine’s Strong Memorial Hospital who is collaborating with Kim on the study believes that sepsis is an underrecognized cause of death and that the incidence is rising with the aging population.
“Sepsis often affects people who are older and whose immune systems are compromised, like cancer patients,” said Pietropaoli, an associate professor of Pulmonary and Critical Care Medicine. “But, it does not discriminate: Young, healthy children can get it and when they do it is like a lightning strike, there is no good way for us to predict it.”
Patients with sepsis are usually hospitalized for several weeks and those who survive feel the repercussions, including frailty, muscle weakness and trouble thinking and concentrating for months or years.
To address the urgent need for new therapies, the National Heart, Lung and Blood Institute and the National Institute of General Medical Sciences created the Blood and Vascular Systems Response to Sepsis Program. The goal of the program is to foster research collaborations that pave the way for the identification of new treatment targets and the development of innovative anti-sepsis therapeutics. Kim and co-lead investigators Richard E. Waugh, Ph.D., chair of the University’s Department of Biomedical Engineering, which includes faculty and staff from the medical school and River Campus, and Jonathan Reichner, Ph.D., professor of Surgery at Rhode Island Hospital and Brown University received the $4 million, five year grant as part of this program.
Scientists have studied leaky blood vessels in sepsis for many years, but the research focused on a single layer of the blood vessel wall called the endothelium. Recent research suggests that there are actually three layers in the vessel wall – the glycocalyx layer, the endothelial cell layer and the basement membrane.
The team will use human cells and mouse models of sepsis to study how immune cells penetrate each layer. Waugh, an engineer by training, will study the glycocalyx layer, Kim will study the endothelial layer and Reichner will study the basement membrane. They’ll bring all their data together to determine how immune cells’ interaction with each layer affects the interaction with the next layer and where and how they might be able to intervene to stop leaks from forming.
“This is truly a multidisciplinary approach, with three main investigators with very different backgrounds bringing their experience and expertise to the table to study a single problem in medicine,” said Stephen Dewhurst, Ph.D., Vice Dean for Research and chair of the Department of Microbiology and Immunology at the School of Medicine and Dentistry. “The work also underscores the importance of our efforts to encourage bridge building across our campus, including collaborations between the School of Medicine and Dentistry and the Hajim School of Engineering and Applied Sciences.”
James McGrath, Ph.D., Young-min Hyun, Ph.D., Elena Lomakina, Ph.D., and Ingrid Sarelius, Ph.D. from the University of Rochester will contribute to the research. Daithi Heffernan, M.D. and Xian O’Brien, Ph.D. from Rhode Island Hospital and Brown University will participate as well.