Progression of lung fibrosis blocked in mouse model

October 5, 2011

A study by researchers at the University of California, San Diego School of Medicine may lead to a way to prevent the progression, or induce the regression, of lung injury that results from use of the anti-cancer chemotherapy drug Bleomycin. Pulmonary fibrosis caused by this drug, as well as Idiopathic Pulmonary Fibrosis (IPF) from unknown causes, affect nearly five million people worldwide. No therapy is known to improve the health or survival of patients.

Their research shows that the RSK-C/EBP-Beta phosphorylation pathway may contribute to the development of lung injury and fibrosis, and that blocking this phosphorylation -- a in which proteins and receptors are switched on or off -- improved Bleomycin-induced in mice. The study appears on-line October 5 in Proceedings of the Library of Science (PloS ONE).

Bleomycin is a common chemotherapy drug used to treat many forms of cancer, according to study authors Martina Buck, PhD, associate professor of medicine, and Mario Chojkier, MD, professor of medicine, both researchers at UC San Diego Moores Cancer Center and the VA San Diego Healthcare System. "Unfortunately, use of Bleomycin has damaging side effects, including lung fibrosis. We are hopeful that this discovery could provide a way to stop such lung damage so that could better tolerate this chemotherapy," said Buck.

The downstream molecular mechanism that causes Bleomycin-induced lung fibrosis remained unknown. The scientists set out to identify the specific signaling involving a single amino acid within a specific domain of one protein that could be blocked the half the progression of such injury, in order to design effective targeted therapeutics.

They found that blocking RSK phosphorylation of a called C/EBP-Beta on the RSK macromolecule Thr217 with either a single or a blocking peptide ameliorated the progression of lung injury and fibrosis induced by Bleomycin in mice.

"We hypothesized that this pathway was critical given similarities between liver and lung fibrogenesis. RSK plays an important role in both the macrophage inflammatory function and survival of activated liver myofibroblasts -- cells that contribute to maintenance and tissue metabolism," said Buck. "Therefore, we proposed that a similar signaling mechanism is also responsible for lung injury and fibrosis."

By identifying the peptide that shuts down this process, the researchers were essentially able to sequester a small piece of an important regulatory protein, C/EBP Beta, responsible for fibrosis, thereby stopping phosphorylation. "Basically, the kinase protein gets hung up, trying again and again -- unsuccessfully -- to 'turn on' the fibrous growth," Buck added.

In addition, phosphorylation of human C/EBP-Beta was induced in human lung fibroblasts in culture and in situ in lungs of patients with severe lung fibrosis, but not in control lungs, suggesting that this signaling pathway may be also relevant in human and fibrosis.

The researchers add that it is premature to assess whether this pathway will provide an effective therapeutic target. However, blocking progression of lung fibrosis could decrease the need for lung transplantation, since IPF is the main indication for lung transplants worldwide.

Explore further: Researchers learn how lung fibrosis begins and could be treated

Related Stories

Researchers learn how lung fibrosis begins and could be treated

June 27, 2011
An invasive cell that leads to fibrosis of the lungs may be stopped by cutting off its supply of sugar, according to researchers at Duke University Medical Center.

Recommended for you

Researchers develop new method to generate human antibodies

July 24, 2017
An international team of scientists has developed a method to rapidly produce specific human antibodies in the laboratory. The technique, which will be described in a paper to be published July 24 in The Journal of Experimental ...

A sodium surprise: Engineers find unexpected result during cardiac research

July 20, 2017
Irregular heartbeat—or arrhythmia—can have sudden and often fatal consequences. A biomedical engineering team at Washington University in St. Louis examining molecular behavior in cardiac tissue recently made a surprising ...

Want to win at sports? Take a cue from these mighty mice

July 20, 2017
As student athletes hit training fields this summer to gain the competitive edge, a new study shows how the experiences of a tiny mouse can put them on the path to winning.

'Smart' robot technology could give stroke rehab a boost

July 19, 2017
Scientists say they have developed a "smart" robotic harness that might make it easier for people to learn to walk again after a stroke or spinal cord injury.

Engineered liver tissue expands after transplant

July 19, 2017
Many diseases, including cirrhosis and hepatitis, can lead to liver failure. More than 17,000 Americans suffering from these diseases are now waiting for liver transplants, but significantly fewer livers are available.

Lunatic Fringe gene plays key role in the renewable brain

July 19, 2017
The discovery that the brain can generate new cells - about 700 new neurons each day - has triggered investigations to uncover how this process is regulated. Researchers at Baylor College of Medicine and Jan and Dan Duncan ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.