Researchers define a new "first step" that initiates sepsis

Feb 9 2006

A Mayo Clinic research team has challenged the accepted theory on the cause of sepsis -- a condition in which the body's cells generate fever, shock and often death. Sepsis is thought to occur when poisons from bacterial infection interfere with the cells.

The Mayo researchers challenge that long-held concept with a new theory in an opinion piece in the current issue of Trends in Molecular Medicine. Their findings suggest that sepsis begins with a change in certain cellular receptors that then provoke widespread inflammation, even in the absence of bacteria or their poisons.

"We think people have been focusing too exclusively on a single causal factor of sepsis for the last 150 years and, as a result, therapeutically aiming at the wrong target -- the bacteria and the poisons they produce," says senior author Jeffrey Platt, M.D. "That's why the death rate remains so high despite efforts to block the poisons."

The researchers define a new "first step" that initiates the sepsis syndrome cycle. In this step, a critical receptor for bacterial poisons and for some of the body's own substances is liberated from "natural suppression." Once free to function, the receptor can trigger the catastrophic cascade of events that is sepsis. The sepsis syndrome can occur during a bacterial infection, as the accepted medical principle holds, or -- as the Mayo Clinic team theory suggests -- it also can occur when substances the body makes act like the bacterial poisons. The Mayo investigators suggest that some or even many cases of sepsis may actually be caused by these normal body substances. The Mayo team argues that this new understanding of how sepsis arises could lead to new treatments for this major medical problem.

Approximately 700,000 cases of sepsis occur annually in the United States, half of which are fatal. Sepsis is the second most common cause for admissions to critical care units and can be a significant complication of some heart surgeries. The Mayo Clinic researchers believe current sepsis treatment isn't more effective because the theory of sepsis is too narrow. Current treatments don't target all causes of sepsis syndrome -- only the bacterial poison cause -- which was described by a 19th century researcher as "the putrid gift."

"Our work is the first to show that this change in receptors in the body is the first true step in the sepsis syndrome, rather than the introduction of a poison," explains Dr. Platt. "The importance then becomes clear. If we really do now have the first cause of sepsis -- not the bacteria, but the unconstrained receptors -- then we can therapeutically interfere with that receptor release mechanism by designing new treatments and possibly, and at long last, develop drugs that treat all cases of sepsis."

Dr. Platt and his colleague, Gregory Brunn, Ph.D., say the evidence they've published compels this conceptual shift about sepsis. "The problem with the concept of sepsis, and what provoked some of our interest, is that it has been known for 10 years that when you treat with anything that interrupts bacterial poisons, it has no impact on the septic disease. That suggests that perhaps the poisons don't cause sepsis after all," Dr. Platt says. "Problems such as this caused us to ask, 'Could there be something else driving sepsis, other than the classic poisoning explanation?'"

Dr. Platt and colleagues discovered several years ago that certain naturally-occurring molecules can stimulate receptors once thought to be exclusive for the bacterial poisons (endotoxins). Once stimulated, the receptors (toll-like receptors) set the sepsis cycle into motion. "This finding was very exciting," notes Dr. Platt. "It explained how the sepsis syndrome can occur when there isn't an infection -- which it does in some cases."

However, Drs. Brunn and Platt saw an obvious problem with this explanation. If normal substances from the body can stimulate toll-like receptors and cause the sepsis syndrome, why aren't we all desperately ill with sepsis? Dr. Brunn explains, "Our bodies are not poised to respond to sepsis. Our bodies are held in check by the fact that this molecule-receptor system is constrained in its activity. What causes sepsis -- and the syndrome like sepsis that can happen in cancer or trauma or in response to drugs -- is that this receptor gets released from its constraint. That's the first step that actually initiates sepsis." Research is underway to discover new therapies that could prevent, blunt or reverse the release of the constrained receptor.