Researchers have found a way to block the ability of white blood cells to sprint toward the sites of infection when such speed worsens the damage done by sepsis, the often fatal, whole-body bacterial infection, according to a study. The results recommend existing drugs as potential new treatments against sepsis, and suggest improvements in the current treatment that would increase its effect while eliminating a treatment-related risk for internal bleeding.

A simple bacterial infection becomes sepsis, or blood poisoning, when it gets bad enough to set off system-wide responses from the body’s immune defenses and blood-clotting system. It becomes septic shock when bacteria, the toxins they produce and the body’s overwhelming immune response cause multiple organ failure. Physicians currently rely on antibiotics and surgical drainage, but new options are urgently needed.

White blood cells called neutrophils fight infection by swarming toward bacteria to engulf and destroy them with toxic molecules. Because these same molecules also damage human cells, this phase of the immune response is carefully contained and quickly shut down. The massive rush of neutrophils seen in sepsis, however, can overcome these restraints. In between infections, dormant neutrophils drift with the bloodstream until they realize they are passing by the part of a blood vessel wall closest to an infection. Proteins on the neutraphil’s surface called integrins then unfold and grab the surface of the blood vessel wall, resisting the flow. The same proteins then help the neutraphil crawl along the tissue scaffold toward the infection site.

In the current study, a team of researchers at the University of Rochester Medical Center demonstrated for the first time that the only approved sepsis drug treatment, recombinant human activated protein C (rhAPC), has its effect by interfering with specific integrins on neutrophil surfaces, which keeps the cells from moving. Importantly, they also learned that a small protein piece of rhAPC, the RGD peptide, is responsible for the treatment’s effectiveness against sepsis.

‘Our results create the distinct possibility that several drugs already approved as safe in humans may have a second use in sepsis,’ said Minsoo Kim, Ph.D., assistant professor of Microbiology and Immunology within the David H. Smith Center for Vaccine Biology and Immunology at the Medical Center, and lead author of the article. ‘That is tremendously exciting because it could dramatically increase the pace at which new treatments for sepsis arrive in the clinic.’

While the standard approach for decades has been to try to kill bacteria with antibiotics, some newer medications are designed to lessen the body’s inflammatory reaction to sepsis. Most of these attempts have failed, but Drotrecogin alpha (brand name Xigris from Eli Lilly), a genetically engineered (recombinant) form human activated protein C (rhAPC), was shown in a recent study to decrease mortality by about six percent, from 31 percent to 25 percent, in severe sepsis patients. Is the only FDA-approved drug for treating severe sepsis and the drug used in the current study.

Before its approval for use in sepsis, rhAPC was known for its ability to prevent blood clots, and researchers thought initially that this ability explained its efficacy against sepsis. When other anti-clotting agents failed to work the same way, however, researchers began looking elsewhere. Research published by Jerry Nick, M.D., and colleagues at the National Jewish Medical and Research Center was the first to suggest that the benefit of rhAPC in sepsis might be explained by its effect on white blood cell migration, not blood coagulation, and several papers followed to confirm the idea. Until the current study, however, no one had been able to show how.

Furthermore, the US Food and Drug Administration earlier this month announced that it was analyzing a report just published in the journal Critical Care Medicine that found Xigris, because of its effect on clotting, may increase the risk of dangerous bleeding in patients with a recent history of hemorrhages.The company argues that the study was flawed, and the drug’s label is very clear about bleeding risk. Whatever the case, Jiang and colleagues are excited because their results argue that the part of Xigris that contributes to bleeding has nothing to do with its effect on sepsis, and can be removed.

Kim’s team tracked the ability of neutrophils to migrate across a glass plate coated with fibronectin. The team placed the neutrophils on the surface and then hit them with a type of molecule produced by bacteria, and toward which neutrophils swarm. The results show that, although neutrophils could sense the bacterial product and had a desire in chemical terms to move toward it, they could not in the presence of rhAPC.

Release Date: February 24, 2009
Source: University of Rochester Medical Center