New Study Finds Key Role For VEGF In Onset Of Sepsis

"Sepsis represents a patient's response to severe infection," explains senior author William C. Aird, MD, Chief of the Division of Molecular Medicine and Associate Director of the Center for Vascular Biology at BIDMC. "We know that antibiotics will take care of the primary infection, but 30 percent of patients with severe sepsis will die in spite of successful antibiotic therapy because the body's host response is out of control and turns on its bearer."

Sepsis develops when the immune system becomes overactivated in response to an existing infection, setting in motion a cascade of dangerous inflammatory and coagulation responses throughout the body. A leading cause of organ failure and intensive care unit (ICU) hospitalizations, severe sepsis accounts for 200,000 deaths each year and poses a particular danger in hospital settings, where patients are more likely to come in contact with antibiotic-resistant pathogens, and when their immune systems have already been weakened by illness or treatments.

"The incidence of severe sepsis is increasing steadily, by about 1.5 percent each year," says Aird, who is also an associate professor of medicine at Harvard Medical School. "This is due, in part, to an aging population and to an improved health care system in which there are an increased number of invasive medical procedures and greater use of immunosuppressive drugs."

Over the past two decades, enormous resources have been expended to test potential sepsis therapies, says Aird. "More than 10,000 patients have been enrolled in more than 20 placebo-controlled, randomized Phase 3 clinical trials, but most of these therapies have thus far failed to reduce mortality rates in patients with severe sepsis," he explains. "It's becoming clear that therapeutic advances for this dangerous syndrome will be contingent upon a better understanding of the causes or pathophysiology of the disease."

Vascular endothelial growth factor, or VEGF, was initially identified as a potent stimulator of endothelial permeability, causing "leakiness" in the endothelial cells that line the body's blood vessels. (The protein is also well-known for its key role in the process of angiogenesis, the growth of new blood vessels as occurs in cancerous tumors and in numerous other diseases and conditions.) VEGF has also been implicated in several inflammatory disease states, including rheumatoid arthritis and inflammatory bowel disease.

Aird has long advocated the importance of the endothelium, the inner cellular lining of blood vessels, in maintaining health and mediating disease. He and his colleagues hypothesized that, in the case of sepsis, VEGF signaling in the endothelium contributes to vascular leakage and inflammation, and thus serves as a key mechanism behind the onset and perpetuation of the syndrome.

Using several animal and human models of the disease, the authors performed a series of experiments to confirm the association between sepsis and circulating levels of VEGF. They then treated animals with protein inhibitors of VEGF or neutralizing antibodies against VEGF receptors, and demonstrated significant protection against morbidity (as measured by cardiac dysfunction, inflammation, coagulation and permeability) and mortality. Based on their findings, they concluded that VEGF plays a pathophysiological role in sepsis and represents a novel therapeutic agent.

"When we first purified this protein in 1983, we named it vascular permeability factor for its profound effects on endothelial barrier function," explains Harold Dvorak, MD, Chief of Pathology Emeritus at BIDMC, whose laboratory is credited with the discovery of VEGF.

"Over the past 20 years, research in the VEGF field has primarily focused on the protein's role in angiogenesis. In many ways, Dr. Aird's study brings us back full circle to an appreciation of the wider role for VEGF in endothelial health and disease," he notes.

"Despite many years of intense research, severe sepsis continues to be associated with an unacceptably high rate of mortality," adds Aird. "Each day in the U.S. between 500 and 600 individuals die from sepsis. Finding an effective therapy to manage this disease is a major priority in the field of health care."

Study coauthors include BIDMC investigators Kiichiro Yano, PhD, Janet M. Mullington, PhD, Shu-Ching Shih, PhD, Hitomi Okada, MSc, Natalya Bodyak, PhD, Peter M. Kang, MD, Bryan Belikoff, BA, Jon Buras, MD, PhD, and S. Ananth Karumanchi, MD; Patricia Liaw, PhD and Lisa Toltl, MSc, of McMaster University, Ontario; Benjamin T. Simms, BA, and Joseph P. Mizgerd, ScD, of the Harvard School of Public Health; and Peter Carmeliet, MD, PhD, of the University of Leuven, Belgium.

This study was supported, in part, by grants from the National Institutes of Health and the National Institute of Mental Health.