Mysteries of a Therapy Unveiled
By Jason Socrates
Bardi
"Nature
loves to hide."
—Heraclitus
of Ephesus, Fragments, circa 500 B.C.
Several years ago, a blood protein called activated protein
C was found to lower the mortality in patients who acquire
severe sepsis. Six months ago, activated protein C was approved
in recombinant form by the Food and Drug Administration for
use in severe sepsis after the protein proved to be effective
at lowering mortality. Today the drug is sold under the brand
name Xigris and is manufactured by Eli Lilly.
Despite its demonstrated efficacy, and despite the fact
that scientists had pondered its beneficial therapeutic effect
for a decade, exactly how activated protein C improved the
prognosis for sepsis had remained a mystery.
Now a group of researchers at The Scripps Research Institute
(TSRI) have described how activated protein C works. The group,
led by TSRI Associate Professor Wolfram Ruf, has elucidated
the signaling pathway through which activated protein C works—the
receptors on the surface of cells it binds to and activates—and
have published these results in one of the latest issues of
the journal Science.
"For the first time," says Ruf, "we know which players are
involved."
The Bacterial Death Knell
Septic shock, also known as sepsis and systemic inflammatory
response syndrome, is a fast-moving, dramatic, and often fatal
disease and is a major problem in U.S. hospitals and hospitals
worldwide.
The prognosis for sepsis is dire. According to the National
Institutes of Health, two percent of all hospital admissions
suffer from sepsis, which typically has a 30 percent mortality
rate and can be as high as 60 percent. Sepsis is one of the
ten leading causes of both infant and adult mortality in the
United States, and directly caused over 30,000 deaths in 1999
alone, according to the Centers for Disease Control and Prevention
(CDC). And the prognosis is especially dire for children.
In a widespread infection, the response of the immune system
is triggered by chemical components of microorganisms, such
as endotoxin in certain bacteria. Endotoxin activates innate
immune cells known as monocytes that induce inflammation at
the site of infection. Monocyte/macrophages release pro-inflammatory
cytokines like TNF-a and Interleukin-6
(IL-6), which makes a person feverish. This inflammation is
necessary because without it, the body cannot fight off the
bacterial infection.
"This is your first line of defense," says Ruf.
The inflammation that fights the infection can spiral out
of control and lead to septic shock syndrome. One of the signs
of severe sepsis is the activation of coagulation within the
vasculature. Platelets disappear and fibrinogen is consumed.
Many different parts of the body can be affected by this consumptive
coagulopathy. Widespread coagulation in the blood vessels
of vital organs leads to blockade of the microcirculation
and whole organs can shut down. Frequently, the vital function
of kidneys and lungs are affected. In patients with sepsis,
the levels of inflammatory cytokines like IL-6 stay high.
"The organ failure is the major problem that results from
the inflammation within the vasculature," says Ruf.
Therapeutic approaches that reduce inflammation proved to
make the patients worse off than they were without treatment
because the therapies compromised their immune response to
the bacteria. For many years, the best treatment has been
to administer broad antibiotics to try to quell the infection,
and the rise of antibiotic-resistant bacteria in the last
few decades has promised to exacerbate the problem.
The Protective Protein Pathway
Several years ago, clinical observations led to the idea
of using protein C as a treatment for sepsis. In certain patients,
particularly in children with severe meningococcal sepsis,
there was a dramatic decrease in the level of activated protein
C in the blood. Researchers thought that if this protein was
disappearing during severe sepsis, perhaps administering it
to patients would help.
And, indeed, that proved to be the case. Activated protein
C fights inflammation without compromising the body's ability
to fight the bacteria and lowers the mortality due to sepsis.
But nobody knew how activated protein C was mediating anti-inflammatory
reactions.
The Ruf laboratory, drawing on several years of work on
related areas of research, figured out the pathway through
which activated protein C works.
The related area that Ruf studies concerns the interaction
of proteins that circulate in the bloodstream and are involved
in the blood clotting cascade with "receptor" proteins, which
are displayed on cells on the inner surface of blood vessels.
The blood clotting cascade is a tightly controlled mechanism
designed primarily to prevent blood loss due to injury, but
is also linked to diseases like cancer and sepsis. During
a bacterial infection, when the monocytes are drawn to a tissue
by the presence of endotoxins, they upregulate a cell surface
receptor, tissue factor, which drives blood clotting. Tissue
factor was shown to be an important contributor to the inflammation
in sepsis by animal experiments that were carried out when
Ruf was a postdoctoral fellow in Thomas Edgington's laboratory.
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