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Anatomy of an Asthma Attack

Blood-borne Tracer Illuminates Patchy Pattern of Constriction

Asthma has become a modern mystery: a disease of complex origins that is becoming increasingly common for reasons not fully understood. For people with asthma, the timing and severity of their next attack can be a personal mystery. A study published online March 16 in Nature offers a new model for understanding the behavior of the asthmatic lung during an attack. The researchers, led by Jose Venegas, HMS associate professor of anesthesia at Massachusetts General Hospital, discovered patterns of constriction in the lung that mimic those seen in complex systems in nature. The model offers a new way to understand how smooth-muscle constriction in the lung can lead to catastrophic changes in lung function.

Photo by Graham Ramsay

Tilo Winkler (left) and Jose Venegas found that their virtual lungs follow some of the same patterns as other complex systems in nature.

When an asthma attack occurs, the smooth muscle that lines the airways contracts, keeping incoming air from reaching the alveoli, where gasses are exchanged. Previous imaging studies on asthmatic lungs have shown that the smooth muscle constricts in large chunks, not uniformly. Venegas’s team explored the patterns of constriction using PET imaging of asthmatic patients undergoing a drug-induced constriction of the airways. The method, which took Venegas a decade to develop, involves injecting a small concentration of the radioactive isotope nitrogen-13 mixed with saline solution into test subjects. Within seconds, the tracer travels through the bloodstream to the lungs and, because nitrogen is highly insoluble in blood, quickly jumps into the airspace of the lungs. When the patient breathes out, the tracer can be seen disappearing from the lungs, lingering in areas that are constricted and poorly ventilated. The blood-borne tracer gets into all airways, unlike an inhaled tracer that would have difficulty penetrating constricted regions. (See a video of this process: PC | Mac.)

The technique allowed the team to quantify the rate at which the tracer left the airways of lungs undergoing constriction. Although the resolution of PET imaging is not very high, for a given unit of space the team could determine whether the tracer was disappearing uniformly or at different rates. This was, in effect, like putting a zoom lens on the areas of constriction and seeing whether they were solid patches or more heterogeneous clusters.
The analysis showed that the large blocks of poor ventilation were dappled with areas that ventilated normally, and there were few gradations in between. “Physiologically, there are two groups of alveolar units: one group that ventilates poorly and one group that ventilates well or faster than normal,” said Venegas.

Spotting Trouble
Ted Wilson, an aerospace engineer and physiologist at the University of Minnesota, had previously developed a model of a single terminal airway—the smallest branching of the bronchial tree that includes alveoli. The model incorporates the physical forces acting on the airway to keep it open, including smooth muscle constriction and the tethering action of the surrounding tissue.

This is “the first realistic, physically sound, and physiologically appropriate model of the asthmatic lung.”

But knowing all the forces in an individual unit does not reveal how patterns emerge in the entire structure. Venegas and postdoctoral fellow Tilo Winkler developed a computer model that could simulate what was happening in the entire bronchial tree. They created an entire set of airways in a tree structure that incorporates the same forces as Wilson’s original model. When the airway branches are laid out in model-perfect symmetry with the smooth muscle activated uniformly across the entire lung, airway narrowing occurs uniformly. But real lungs are more complex, so the team introduced a small imperfection: they varied the thickness of the airway wall by one percent at random locations throughout the lung. With this small heterogeneity, much less than the real asymmetries of the lung, regions of patchy constriction bloomed as the muscle constricted.

After searching for similar patterns emerging from nonlinear systems, Venegas and his colleagues came across a phenomenon called “self-organized patchiness” that is used to explain behaviors in ecosystems, such as the stripes, spots, and labyrinths formed by vegetation in arid climates. These systems have in common a bistability between two attracting states—in the case of lungs, the alveoli constricting or remaining open. When patterns of patchiness emerge in bi-stable systems in response to a decrease in resources, they signal that a catastrophic shift is about to occur from one state to another. All lungs have the propensity to form these patterns, but only if they experience constriction of the smooth muscle.

Tipping Point
Bela Suki, associate professor of bioengineering at Boston University, calls the work “the first realistic, physically sound, and physiologically appropriate model of the asthmatic lung.” Though the model does not address what causes asthma in the first place, it demonstrates how a very small trigger can result in a widespread effect. “We simply better understand how an asthma attack occurs,” said Suki, who is not an author on the paper. The model also sheds light on why some patients stop responding to inhaled bronchodilators during severe attacks. Once there is a catastrophic shift in lung function, the dilators can only reach the spaces that are still ventilated, but cannot rescue the entire system.

Breathtaking. A model of human lungs reveals a system whose function is shaped by sudden shifts and its own physiological history. In this illustration, decreasing the tidal volume of the lungs by taking smaller breaths (left) in the presence of smooth mus-cle constriction causes large patchy regions of the lung to stop ventilating (black) in sudden shifts. When breath intake is then increased again (right) the lungs do not bounce back completely, so regions of poor ventilation remain. (Image courtesy of Jose Venegas)

The study also adds data to a debate about which regions of the lung are responsible for poor ventilation. It had been assumed that the ends of the branches close to where gas is exchanged were most important for creating an asthma attack. An experimental technique called bronchial thermoplasty has succeeded in relieving asthma by burning out the smooth muscle of the larger airways in patients, suggesting that it is the larger airways that matter. This model shows there may be feedback between the large and small airways that magnifies the resulting constriction.

Venegas said that the study is an example of how the behavior of a system cannot be predicted by the behavior of its parts. “The model allows you to understand the essence of what you’re seeing and realize that the clustering of the lung in large regions is a result of the way the lungs behave,” he said. “Healthy normal lungs to asthmatic lungs, they all have an inherent propensity to form these clusters because of an inherent instability in the design.”

—Courtney Humphries

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