Modified Protein May Lead To First Cure For Cirrhosis Of The
Liver ScienceDaily (Dec. 28, 2007) -- University of
California, San Diego researchers have proven in animal
studies that fibrosis in the liver can be not only stopped,
but reversed. Their discovery, to be published in PLoS Online
on December 26, opens the door to treating and curing
conditions that lead to excessive tissue scarring such as
viral hepatitis, fatty liver disease, cirrhosis, pulmonary
fibrosis, scleroderma and burns.

Six years ago, the UC San Diego School of Medicine research
team discovered the cause of the excess fibrous tissue
growth that leads to liver fibrosis and cirrhosis, and
developed a way to block excess scar tissue in mice. At that
time, the best hope seemed to be future development of a
therapy that would prevent or stop damage in patients
suffering from the excessive scarring related to liver or
lung disease or severe burns.

In their current study, Martina Buck, Ph.D., assistant
professor of medicine at UCSD and the Veterans Affairs San
Diego Healthcare System, and Mario Chojkier, M.D., UCSD
professor of medicine and liver specialist at the VA, show
that by blocking a protein linked to overproduction of
scar tissue, they can not only stop the progression of
fibrosis in mice, but reverse some of the cell damage that
already occurred.

In response to liver injury -- for example, cirrhosis caused
by alcohol -- hepatic stellate cell (HSC) activated by
oxidative stress results in large amounts of collagen.
Collagen is necessary to heal wounds, but excessive collagen
causes scars in tissues. In this paper, the researchers showed
that activation of a protein called RSK results in HSC
activation and is critical for the progression of liver
fibrosis. They theorized that the RSK pathway would be a
potential therapeutic target, and developed an RSK inhibitory
peptide to block activation of RSK.

The scientists used mice with severe liver fibrosis -- similar
to the condition in humans with cirrhosis of the liver -- that
was induced by chronic treatment with a liver toxin known to
cause liver damage. The animals, which continued on the liver
toxin, were given the RSK- inhibitory peptide. The peptide
inhibited RSK activation, which stopped the HSC from
proliferating. The peptide also directly activated the caspase
or "executioner" protein, which killed the cells producing
liver cirrhosis but not the normal cells.

"All control mice had severe liver fibrosis, while all mice
that received the RSK-inhibitory peptide had minimal or no
liver fibrosis," said Buck.

Buck explained that the excessive collagen response is blocked
by the RSK-inhibitory peptide, but isn't harmful to the liver.
"The cells continue to do their normal, healing work but their
excess proliferation is controlled," Buck said. "Remarkably,
the death of HSC may also allow recovery from liver injury and
reversal of liver fibrosis."

The researchers found a similar activation of RSK in activated
HSC in humans with severe liver fibrosis but not in control
livers, suggesting that this pathway is also relevant in human
liver fibrosis. Liver biopsies from patients with liver
fibrosis also showed activated RSK.

The study expands on work reported in 2001 in the journal
Molecular Cell announcing that a team led by Buck had found
that a small piece of an important regulatory protein called
C/EBP beta was responsible for fibrous tissue growth, or
excessive scar tissue following injury or illness. When
normal scarring goes awry, excessive build-up of fibrous
tissue can produce disfiguring scars or clog vital internal
organs and lead to serious complications. Buck and colleagues
developed a mutated protein that stopped this excessive
fibrous tissue growth.

"Six years ago, we showed a way to prevent or stop the
excessive scarring in animal models," said Buck. "Our latest
finding proves that we can actually reverse the damage."

Worldwide, almost 800,000 people die from liver cirrhosis each
year, and there is currently no treatment for it. Excessive
tissue repair in chronic liver disease induced by viral,
toxic, immunologic and metabolic disorders all result in
excessive scar tissue, and could benefit from therapy
developed from the UCSD researchers' findings.

The research was supported by grants from the National
Institutes of Health, the Department of Veterans Affairs and
UCSD's Medical Research Foundation. Buck is the recipient of a
Howard Temin Award from the National Cancer Institute.