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MEDICINE Breathing New Life into Asthma TherapyCells' Response to Stress Points To Modified Treatment A bout of asthma can leave a person spent and shaken, but scientists have recently uncovered a more lasting consequence. During an attack, the delicate airways in the lungs—the tiniest of which give rise to the grapelike alveoli—can grow permanently scarred, making future attacks even more debilitating. Figuring out what causes these airways to be remodeled, and how to stop it, is one of the most active quests in asthma research.
During an asthmatic attack, smooth muscles encircling the lung's airways constrict, causing the normally smooth layer of epithelial cells lining the airways to invaginate and bunch up on themselves, producing a corrugated appearance (above). The mechanical forces produced by the compression of the epithelial cells (see arrows below) cause the cells to upregulate genes that lead, ultimately, to airway stiffening. Courtesy of Jeffrey Drazen
A team of HMS scientists has hit upon a novel explanation for how this airway remodeling occurs, one that suggests a revised approach to asthma treatment. Signal SourcesUntil recently, suspicions have centered on the immune cells. Asthma begins when these cells signal the smooth muscles encircling the lung's airways to constrict. Researchers thought that during an attack, the immune cells might send a second set of messages, this time to the epithelial cells lining the airways, ultimately causing the airways to stiffen.It now appears that another force may be working on the epithelial cells, namely the mechanical stress exerted upon them by the constricting smooth muscles. As these muscles tighten, epithelial cells are squeezed and deformed. Jeffrey Drazen and his colleagues have evidence that the cells sense this deformation and send messages to nearby cells, telling them to produce stiffening proteins, perhaps to resist the stranglehold. Led by Melody Swartz, who was until recently a research fellow in Drazen's lab, the researchers grew human epithelial cells together with fibroblasts, which are responsible for making collagen and other airway-thickening proteins. Swartz, who is now at Northwestern University, and her colleagues exposed the epithelial cells to the kind of mechanical stress they might experience during an asthma attack. They found that the fibroblasts secreted fibrous proteins. When the stress was removed, the fibroblasts failed to produce the proteins. The findings, which appear in the May 15 Proceedings of the National Academy of Sciences, suggest that during an asthma attack, stressed epithelial cells are sending signals to the collagen-producing fibroblasts. Tuning into this mechanically induced cellular conversation may lead to a new therapeutic approach, or rather, the revival of an old one—namely, the use of muscle relaxants. For decades, asthma was treated with drugs that loosen the smooth muscle's grip on the lungs' airways. These muscle relaxants were discarded about 20 years ago in favor of anti-inflammatory agents, which help stop immune cells from instigating an attack. But these steroids are not completely effective. Adding muscle relaxants could help break the cycle of attack, constriction, and stress-induced scarring.
A study by researchers including Jeffrey Drazen (left) and Dan Tschumperlin suggests that muscle relaxants might be combined with steroids to produce an improved asthma treatment. Photo by Graham Ramsay "I would argue from this work that muscle relaxants should be combined with anti-inflammatory medicines, because by preventing smooth muscle constriction, they would prevent this amplification from occurring in the first place," said Drazen, an HMS professor of medicine at Brigham and Women's Hospital and editor in chief of the New England Journal of Medicine. Such combined therapies—steroids and muscle relaxants in the same inhaler—are already used in Europe. Although the combined therapy has met with some resistance in the U.S., Drazen hopes that the new work will provide a rationale for the incorporation of muscle relaxants. "People have viewed preventing bronchoconstriction as being a physiological treatment," he said. "They thought it had no effect on the cell biology. These data suggest that this physiological treatment actually has a substantial impact on the cell biology of the airways." Stress ResponseIt was a sense that such therapies—in particular, a new class of long-acting muscle relaxants—were being unfairly dismissed that inspired Drazen to take a closer look at the effects of bronchoconstriction on human epithelial cells. He and his colleagues had previously shown that applying mechanical pressure to rat epithelia caused the cells to turn up the expression of certain genes (see figure). Suspecting that it might do the same in human epithelial cells and that the upregulation might be directed at signaling fibroblasts to make collagen and other airway-thickening proteins, Swartz cultured the two kinds of human cell together.Sure enough, when the epithelial cells were mechanically stressed, collagen levels went up. At the same time, fibroblast proliferation slowed down, suggesting that the epithelial cells were signaling each fibroblast to make extra protein. But in addition to signaling the fibroblasts, epithelial cells put out two enzymes—MMP-9, which degrades collagen, and TIMP-1, which inhibits MMP-9, thereby preserving collagen. In people with asthma, the ratio between the two enzymes is tipped in favor of the collagen-preserving TIMP-1. The experimentally stressed epithelial cells exhibited the asthmalike ratio. This raises an interesting set of possibilities. "Either the fibroblasts are producing more collagen on a per-cell basis when we apply the stimulus or the epithelial cells are modulating their enzyme system to allow more collagen to be elaborated in the medium," said Dan Tschumperlin, research fellow in physiology in the Department of Environmental Health at HSPH and a co-author on the paper. He is currently studying the signals sent by the epithelial cells to the fibroblasts to see if any are capable of upregulating collagen production. It is unlikely those signals will tell the whole story. In another experiment, the researchers exposed isolated fibroblasts to culture medium containing the mechanically induced epithelial signals, but no epithelial cells. Fibroblast proliferation increased, whereas it slowed down in the presence of epithelial cells. The findings suggest that there is an ongoing dialogue between fibro-blasts and epithelia. "The fibroblasts are somehow communicating with the epithelial cells as well as the epithelial cells communicating with the fibroblasts," said Tschumperlin. What kind of communication might be occurring between the two kinds of cell? "If you think of this as a mechanism to stiffen the airway and therefore prevent it from constricting, perhaps this two-way communication allows the epithelial layer to know everything is OK—or not OK," said Drazen. "So you don't just have cells saying 'remodel.' Other cells need to be able to say 'this area needs amplification, or shoring up, and this area needs downregulation.'" —Misia Landau |
