June 24, 2004 ANN ARBOR, Mich. – Inflammation, with its associated redness, swelling and pain, is a double-edged sword. It helps the body to heal and to defend itself against invading pathogens. But uncontrolled inflammation can attack and destroy the body's own tissue. In the lungs, this produces a deadly condition called chronic obstructive pulmonary disease, or COPD.
To control inflammation, the body maintains a finely-tuned balance between the activity of pro- and anti-inflammatory genes and their proteins. Peter A. Ward, M.D., the Godfrey D. Stoebbe Professor of Pathology in the University of Michigan Medical School, is trying to understand the intricacies of this complex balancing mechanism. His goal is to help scientists develop new therapeutic drugs to treat immune-related diseases like COPD.
In research results from a series of experiments, published June 15 in the Journal of Immunology, Ward and his colleagues reported the presence of an anti-inflammatory protein called Stat3 in laboratory rats with severe lung inflammation.
Stat3 is the subject of intense scientific investigation, because it's known to be an important transcription factor that turns on genes required for the division, growth and death of cells. Now, U-M scientists have discovered that it appears to regulate the inflammatory response in lungs, as well.
"Our study found that Stat3 is activated in the lung following acute lung injury, and seems to serve as an intermediary agent for anti-inflammatory cytokines (immune system messenger proteins) during lung injury," says Hongwei Gao, M.D., Ph.D., a U-M research fellow in pathology and first author on the paper. "This is the first study to suggest this function for Stat3 in lung tissue.
"We were interested in Stat3, because several recent studies have shown that it plays an important role in inflammation," adds Gao. "For example, in animal models of sepsis – a systemic, uncontrolled inflammatory response – Stat3 proved to be the most important mediator of anti-inflammatory signals in macrophages. In addition, hematopoietic-specific Stat3 knock-out mice develop progressive inflammatory bowel disease, which is usually fatal."
To trigger an inflammatory reaction, U-M scientists deposited substances called IgG immune complexes in the airways of laboratory rats in the study. The rats' immune system responded by flooding the damaged lung tissue with immune cells called neutrophils and macrophages, which generate a cascade of proteins and other factors to start the tissue healing process. After the procedure, U-M scientists removed the lungs and analyzed them to determine the location, timing and amount of proteins produced during the inflammatory reaction.
Gao, Ward and colleagues found Stat3 protein produced in rat lungs after tissue injuries were induced by IgG immune complexes. They also found that Stat3 activation depended on the presence of macrophages, neutrophils and cytokines called Interleukin-6 and Interleukin-10. They also noted the presence of a protein called Socs3, which suppresses cytokine signaling, and a protein called C5a, which appears to trigger production of regulatory proteins.
"What we've found here is a system that regulates the inflammatory response and prevents excessive activation of the entire system," Ward says. "If you block any of the products in this pathway, the ability to regulate the inflammatory response is lost. Essentially, this means there is no end to the intensity of the response, and it becomes extremely tissue damaging."
Scientists researching new therapeutic drugs to treat immune-related diseases usually try to block specific pro-inflammatory agents to prevent an immune reaction. But Ward takes the opposite approach. Rather than blocking the pro-inflammatory pathway, he wants to enhance the activity of Stat3, Socs3 and other natural anti-inflammatory proteins.
"Our strategy is to take advantage of knowledge about natural inhibitors that regulate the inflammatory response," Ward says. "It's very different than the standard anti-inflammatory approach."
Ward explains that new treatments for inflammation-induced tissue damage are especially needed in chronic obstructive pulmonary disease, because COPD patients don't respond to the anti-inflammatory effects of steroid drugs like cortisol. Non-steroidal anti-inflammatory drugs, like Vioxx and Celebrex, treat symptoms, but do nothing to stop the progressive tissue destruction.
"There's a real need for powerful, reasonably-priced anti-inflammatory drugs that can be used across the board in rheumatoid arthritis, lupus, COPD and other inflammatory diseases," Ward adds. "If we can find a way to induce the activity of genes and proteins like Stat3 with anti-inflammatory effects, pharmaceutical companies may be able to use that knowledge to develop a new generation of anti-inflammatory therapeutic drugs."
The U-M research was supported by the National Institutes of Health. Additional co-authors on the paper from the U-M pathology department included Ren-Feng Guo, M.D., assistant research scientist; Cecilia L. Speyer, Jayne Reuben, Thomas A. Neff, Niels C. Riedemann, and L. Marco Hoesel, research fellows; Shannon D. McClintock and Firas S. Zetoune, research associates; J. Vidya Sarma, Ph.D., research assistant professor; and Nico Van Rooijen, Ph.D., from Vrije Universiteit in Amsterdam, The Netherlands.
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