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Study Suggests New Approach To Asthma

Date:
April 30, 1999
Source:
Washington University School Of Medicine
Summary:
Although most scientists regard immune cells as the culprit in asthma, a new study suggests that resident airway cells may be at fault. These cells contain an anti-virus alarm system which, if not turned off, triggers persistent inflammation.

St. Louis, April 28, 1999 -- Although most scientists regard immune cells as the culprit in asthma, a new study suggests that resident airway cells may be at fault. These cells contain an anti-virus alarm system which, if not turned off, triggers persistent inflammation.

"I think this will change the way people think about asthma," says Michael J. Holtzman, M.D., head of the research team. "And it suggests therapeutic strategies that have not previously been considered."

Holtzman is the Selma and Herman Seldin Professor of Medicine, director of the Division of Pulmonary and Critical Care Medicine and associate professor of cell biology and physiology at Washington University School of Medicine in St. Louis. His team will report its findings in the May 1 issue of the Journal of Clinical Investigation (JCI). Lead author Deepak Sampath, Ph.D., was one of Holtzman's graduate students and now is a researcher with Wyeth-Ayerst.

Twenty years ago, Holtzman obtained the first evidence that the epithelial cells that line our airways may actively defend the body against infection. "Now it seems that these cells are in fact specially programmed for host defense and are abnormally programmed in people with asthma," he says.

He questions the traditional view that asthma is entirely an allergic response. In this scenario, an allergen such as dust or mold provokes immune cells to secrete chemicals -- cytokines -- that rally more immune cells to the site, triggering inflammation.

Holtzman notes that many asthmatic patients don't suffer from allergies and that most patients with allergies don't develop asthma. "That suggests some other contributing event," he says.

He has focused on one of the cellular signaling pathways that is controlled by molecules in the JAK/STAT family. This pathway responds to cytokines released during viral infection. When it is activated, a protein called Stat1 moves into the nucleus and switches on certain genes. The products of these genes attract immune cells to fight the virus.

The JCI paper suggests that the same JAK/STAT pathway plays a key role in asthma by operating even in the absence of viral infection.

First, the researchers located Stat1 in epithelial cells they had brushed from people's airways and in biopsy samples of the airway lining. In healthy subjects and subjects with chronic bronchitis, Stat1 was usually in the cytoplasm, where it presumably was inactive. But in samples from 24 people with asthma, it was usually in the nucleus, presumably switching on genes.

Stat1 enters the nucleus after one of the JAK proteins gives it a phosphate group. The researchers found phosphorylated Stat1 in epithelial cells brushed from the asthmatic subjects. But the protein was not phosphorylated in immune cells retrieved from the airway or in either cell type from the nonasthmatic subjects. Other proteins that switch on inflammation-triggering genes were not phosphorylated in any of the samples.

The researchers then looked for consequences of Stat1 activation, focusing on the products of genes Stat1 is known to turn on. They found abnormally high levels of three inflammatory proteins in cells brushed from the airway. These were Stat1 itself, ICAM-1, which makes immune cells stick to the airway, and a protein that regulates interferon production. Levels of ICAM-1 correlated with the number of immune cells (mostly T cells) in the biopsy samples.

Finally, the researchers looked for the cause of Stat1 activation.

Interestingly, interferon-gamma, a critical anti-viral mediator and the normal trigger for epithelial Stat1 activation, was present only at the usual low level found in subjects with asthma.

"These findings, along with others we've made in the past several years, strongly suggest that this epithelial signaling pathway is unnecessarily activated in people with asthma," Holtzman says. "In contrast to what has been presented in the past, asthma appears to be linked to abnormal cytokine signaling rather than to a change in cytokine production. Also, the abnormality appears to be localized to a cellular pathway that was not supposed to be part of this disease. Reprogramming of these controls for epithelial immune-response genes helps explain several missing pieces of the asthma story."

In this regard, Holtzman says, the findings offer the first example linking abnormal behavior of JAK/STAT pathways for cytokine signaling to the development of an inflammatory disease.

Activation of the JAK/STAT pathway appears to be fundamental to asthma, Holtzman says, because it was seen in all of the asthmatic subjects regardless of whether they had allergies or were taking corticosteroids, which suppress allergic symptoms.

Holtzman's previous work has suggested a way to dampen the JAK/STAT pathway and hopefully to alleviate asthma. He and his colleagues discovered that adenovirus, which causes respiratory infections, can sabotage the airway cells' inflammatory response by preventing Stat1 from activating genes. So an aerosol of genetically altered adenovirus that could stop asthma without compromising immunity might be a potential therapy. "The virus has taken advantage of us," Holtzman says, "so perhaps we could take advantage of the virus."

Grants from the National Institutes of Health and the Alan A. and Edith L. Wolff Charitable Trust supported this research.

###

Sampath D, Castro M, Look DC, Holtzman MJ. Constitutive activation of an epithelial signal transducer and activator of transcription (STAT) pathway in asthma. Journal of Clinical Investigation, 103, 1353-1361.


Story Source:

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


Cite This Page:

Washington University School Of Medicine. "Study Suggests New Approach To Asthma." ScienceDaily. ScienceDaily, 30 April 1999. <www.sciencedaily.com/releases/1999/04/990430070755.htm>.
Washington University School Of Medicine. (1999, April 30). Study Suggests New Approach To Asthma. ScienceDaily. Retrieved August 27, 2014 from www.sciencedaily.com/releases/1999/04/990430070755.htm
Washington University School Of Medicine. "Study Suggests New Approach To Asthma." ScienceDaily. www.sciencedaily.com/releases/1999/04/990430070755.htm (accessed August 27, 2014).

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