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Plugging leaks: manipulating receptors may impede sepsis.

Using synthetic molecules that bind to signaling proteins on blood vessel cells, scientists have discovered a way to subdue sepsis in mice. They report that activating or disabling the proteins affects the course of sepsis and could provide a way to combat this deadly condition.

Sepsis develops when a blood infection triggers a runaway immune reaction. Patients often become listless or unconscious and show a high fever, rapid heartbeat, and falling blood pressure. Internally, blood leaks through their vessel walls, a catastrophic event that swells nearby tissues. Fluid collects in the lungs, and sluggish blood flow starves organs of nourishment.

Despite decades of research, the biology underlying sepsis has never been fully sorted out, says Athan Kuliopulos, a physician and biochemist at the Tufts University School of Medicine in Boston. Since sepsis has resisted numerous attempts at treatment, some scientists suspect that leakage might stem from some peculiarity of the cells lining blood vessels.

In the 1990s, scientists discovered a protein called protease-activated receptor 1 (PAR1) and three sister proteins on blood vessel cells. As a receptor protein, PAR1 signals its cell when bound by a molecule that fits it.

A receptor typically issues a consistent, predictable signal when activated. "We hypothesized that PAR1 might be changing its role," in sepsis, Kuliopulos says.

He and his colleagues devised synthetic compounds that bind to the receptor, allowing them to switch it on or off. They then tested the compounds in mice with sepsis. When PAR1 was switched off at the onset of sepsis, 60 percent the mice survived. Among mice given a PAR1 activator at the start, nearly all died.

In mice that had had sepsis for 4 hours, PAR1 indeed seemed to reverse its role. These mice fared better if PAR1 was activated, but succumbed when it was shut down, the researchers report online and in the December Nature Immunology. Further tests showed that sepsis caused leakage in blood vessels in the lungs and that manipulation of PAR1 could limit that damage.

Such leakage results when vessel-lining cells detach from one another. In a separate set of experiments, the researchers found that activation of both PAR1 and a sister receptor, PAR2, is necessary for these cells to restore the lining. In mice engineered to lack PAR2, reactivating PAR1 did not cause vessel linings to reassemble.

The new study makes "a reasonable case that in sepsis ... the activation of PAR1 has both damaging effects and protective effects, depending on the circumstances," says pathologist Peter A. Ward of the University of Michigan Medical School in Ann Arbor.

If tests in healthy people show that the antisepsis compounds are safe, Ward says, a second-stage trial might test them in gravely ill patients. But, he cautions that becanse of PAR1's role-reversal propensity, "it might be very tricky."
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Title Annotation:This Week
Author:Seppa, Nathan
Publication:Science News
Date:Nov 3, 2007
Words:463
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