Paradox in the lungs resolved

October 02, 2003

Researchers at National Jewish Medical and Research Center have discovered that a single class of molecules serves as the immune system's gatekeeper in the lungs, damping the immune response in some situations and promoting it in others.

The findings, published in the October 3 issue of the journal Cell, resolve an apparent paradox that prevented researchers from understanding how these versatile surveillance proteins function.

"The lung collectins can effectively discriminate between conditions in the lung that warrant an immune response and those that do not," said Peter Henson, Ph.D., Professor of Pediatrics at National Jewish Medical and Research Center. "They do this with a clever mechanism, inhibiting the immune response with one end of their structure and promoting it with the other."

The immune system must ride a fine line in its protection of the lung, whose surface area covers an area about the size of a tennis court. It must quickly sound the alarm when it detects a potentially harmful organism or molecule. But it must also tolerate a certain amount of irritation without calling out the inflammatory, disease-fighting tools, that can cause damage themselves.

The two lung collectins, surfactant proteins A and D (SP-A and SP-D), are widely recognized as members of the innate immune system, sentinels capable of initiating an inflammatory response to overcome infections and promote tissue repair.

However, recent experiments with mice contradicted this widely held view and raised serious questions about the role of the lung collectins. Mice engineered to lack the lung collectins actually demonstrate an enhanced inflammatory response, while mice overexpressing the lung collectins exhibited a reduced inflammatory response.

In their paper, Dr. Henson and his colleagues resolved this paradox with experiments showing that the lung collectins actually play two roles in the lungs, damping the immune response in some situations and promoting it in others. They showed that one end of the lung collectins binds to a molecule on lung cells that suppresses inflammation. But that same end of the lung collectins can recognize and binds to fragments of foreign microorganisms. When it does, the other end of the lung collectin binds to receptors on the cells that promote inflammation.

"These findings should help clarify confusion about the lung collectins," said Henson. "Lung collectins play not one role, but two as they protect the lung not only from harmful pathogens, but also from harmful overreaction by the immune system."
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National Jewish Medical and Research Center is a nonprofit, nonsectarian institution dedicated to research and treatment of respiratory, allergic and immune-system diseases, including asthma, tuberculosis, emphysema, severe allergies, lupus and other autoimmune diseases.

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