[tt] Researchers halt, reverse cirrhosis of the liver | Science Blog

[Brian Atkins]

http://www.scienceblog.com/cms/researchers-halt-reverse-cirrhosis-liver-15104.html

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.

 From http://www.ucsd.edu

-- 
Brian Atkins
Singularity Institute for Artificial Intelligence
http://www.singinst.org/