Featured Research

from universities, journals, and other organizations

Mouse model of debilitating lung disease suggests potential treatment regimen

Date:
October 3, 2012
Source:
University of Pennsylvania School of Medicine
Summary:
Researchers have developed a new mouse model of LAM (pulmonary lymphangioleiomyomatosis), producing a way to study disease etiology and develop drugs.

LAM, short for pulmonary lymphangioleiomyomatosis, affects about 1 in 10,000 women of childbearing age and is characterized by proliferation of smooth muscle-like cells in the lung, destruction of lung tissue, and growth of lymphatic vessels. The disease is caused by inactivation of either of two genes, TSC1 or TSC2, but to date no animal model has been able to replicate the pathologic features those mutations produce in humans.

Now, researchers at the Perelman School of Medicine at the University of Pennsylvania report in Science Translational Medicine a new mouse model of LAM that does replicate those features, producing a way to study disease etiology and develop drugs. What's more, two readily available drugs -- an antibiotic and a statin -- may help to treat, and maybe reverse, symptoms.

Elena Goncharova, PhD, research assistant professor of Medicine, and Vera Krymskaya, PhD, associate professor of Medicine, Pulmonary, Allergy, and Critical Care Division at Penn, led the study. The team collected TSC2-mutant cells from spontaneous kidney tumors formed in mice. They then "sensitized" those cells by growing them into tumors in immunocompromised mice, excising those tumors, and reinjecting their cells into the tail veins of another set of immunocompromised mice.

Unlike non-sensitized TSC2-deficient cells, the sensitized cells produced multiple lung nodules composed of smooth muscle-like cells, as in the human disease, as well as destruction of lung tissue and lymphangiogenesis. These nodules also exhibited enhanced activity of an enzyme called matrix metalloproteinase and the loss of elastin, suggesting a potential mechanism for causing that tissue damage. The study also demonstrated for the first time that destruction of lung tissue in LAM is caused by TSC2 deficiency in lung lesions.

TSC1 and TSC2 regulate the mTOR (mammalian target of rapamycin) pathway. As a result, the antibiotic rapamycin is already used therapeutically for pulmonary LAM. But, says Goncharova, the drug appears only to halt cell growth, not induce cell death. When rapamycin is removed, disease progresses. "That showed us that something else was needed to fully treat the disease," she says.

As it turns out, that something else could be a statin.

Statins are well known cholesterol-controlling medications. But they also can inhibit signaling proteins called GTPases, inducing cell death. An earlier study using rapamycin and simvastatin demonstrated that the combination could prevent tumor reoccurrence in a mouse model in which TSC2-mutant tumors were not grown in the lungs, but in the flanks of the animal.

The current study expands that observation, demonstrating that rapamycin plus simvastatin can inhibit the growth of TSC2-mutant tumors in the mouse lung, as well as the resulting tissue damage.

But perhaps more importantly, from a clinical point-of-view, application of the drugs after development of lung nodules and tissue damage could actually reverse tissue damage.

"It's my strong belief that if you want to propose treatment options, you need to reverse or attenuate existing disease. Prevention is not enough," says Goncharova.

As in the earlier study, rapamycin in this study appears to be cytostatic -- it halts cell growth; simvastatin induces cell death, and both drugs block matrix metalloproteinases as well. Both drugs are FDA-approved and commercially available.

But before pulmonary LAM patients call their physicians for a prescription, Goncharova stresses that the results were in mice, not humans. Clinical trials are required to test the efficacy of this drug combination in patients. To date, no such trials have been initiated.

"I hope it will be done in the near future," she says.

Other co-authors from Penn include Dmitry Goncharov, Melane Fehrenbach, Irene Khavin, Blerina Ducka, Angela Haczku, and Steven Albelda.

The study was supported by the National Heart, Lung, and Blood Institute (RO1HL71106, RO1HL090829, RO1HL114085), Abramson Cancer Center Core Support Grant (NIH P130-CA-016520-34, P30ES013508, RO1AI072197, RC1ES018505), the American Lung Association (CI-9813-N), the LAM Foundation, and the Auckland Medical Research Foundation.


Story Source:

The above story is based on materials provided by University of Pennsylvania School of Medicine. Note: Materials may be edited for content and length.


Journal Reference:

  1. Elena A. Goncharova, Dmitry A. Goncharov, Melane Fehrenbach, Irene Khavin, Blerina Ducka, Okio Hino, Thomas V. Colby, Mervyn J. Merrilees, Angela Haczku, Steven M. Albelda, and Vera P. Krymskaya. Prevention of Alveolar Destruction and Airspace Enlargement in a Mouse Model of Pulmonary Lymphangioleiomyomatosis (LAM). Sci Transl Med, 3 October 2012 4:154ra134 DOI: 10.1126/scitranslmed.3003840

Cite This Page:

University of Pennsylvania School of Medicine. "Mouse model of debilitating lung disease suggests potential treatment regimen." ScienceDaily. ScienceDaily, 3 October 2012. <www.sciencedaily.com/releases/2012/10/121003141402.htm>.
University of Pennsylvania School of Medicine. (2012, October 3). Mouse model of debilitating lung disease suggests potential treatment regimen. ScienceDaily. Retrieved April 24, 2014 from www.sciencedaily.com/releases/2012/10/121003141402.htm
University of Pennsylvania School of Medicine. "Mouse model of debilitating lung disease suggests potential treatment regimen." ScienceDaily. www.sciencedaily.com/releases/2012/10/121003141402.htm (accessed April 24, 2014).

Share This



More Health & Medicine News

Thursday, April 24, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Deadly Fungus Killing Bats, Spreading in US

Deadly Fungus Killing Bats, Spreading in US

AP (Apr. 24, 2014) A disease that has killed more than six million cave-dwelling bats in the United States is on the move and wildlife biologists are worried. White Nose Syndrome, discovered in New York in 2006, has now spread to 25 states. (April 24) Video provided by AP
Powered by NewsLook.com
Companies Ramp Up Wellness to Lower Health Costs

Companies Ramp Up Wellness to Lower Health Costs

AP (Apr. 24, 2014) That little voice telling you to exercise, get in shape and get healthy is probably coming from your boss. More companies are beefing up wellness programs to try and cut down their health care costs. (April 24) Video provided by AP
Powered by NewsLook.com
Blood From World's Oldest Woman Suggests Life Limit

Blood From World's Oldest Woman Suggests Life Limit

Newsy (Apr. 24, 2014) Scientists say for the extremely elderly, their stem cells might reach a state of exhaustion. This could limit one's life span. Video provided by Newsy
Powered by NewsLook.com
FDA Wants To Ban Sales Of E-Cigarettes To Minors

FDA Wants To Ban Sales Of E-Cigarettes To Minors

Newsy (Apr. 24, 2014) The Food and Drug Administration wants to crack down on the use of e-cigarettes, banning the sale of the product to minors. Video provided by Newsy
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins