Fibrosis News

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From UC San Diego:

News Release

Date: December 27, 2007

Researchers Show that Fibrosis can be Stopped, Cured and Reversed

Modified Protein Developed by UC San Diego Researchers May Lead to

First Cure for Cirrhosis of the Liver

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, a Buck, Ph.D., assistant professor of

medicine at UCSD and the Veterans Affairs San Diego Healthcare System,

and 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 Temin Award from the

National Cancer Institute.

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Media Contact: Debra Kain, , ddkain@...

UIP/LCH 5.06 CA