Many public garages and park-and-pay parking lots have a device to foil park-and-run deadbeats. It consists of a row of sharp metal teeth that lie level across the entrance with the roadway. Cars easily enter the lot, but if a vehicle attempts to exit over that entrance thus avoiding the payment booth the teeth slash its tires.

Like so many clever mechanical inventions, this one was anticipated by Mother Nature in her case, by the mammalian lung. Clinical pulmonologist and research immunologist David Corry makes the point in experimental mice: “Asthma is characterized by lots of inflammation of the lungs, lots of inflammatory cells, and some key physiologic changes including airway obstruction. That causes shortness of breath and even death from the airway obstruction, which is actually produced by the inflammation. That’s what makes asthma a disease.

“In animals lacking a gene encoding an enzyme called MMP2 (matrix metalloproteinase),” Corry continued, “the inflammation is not cleared. It builds up to very high levels in the lungs of these [Knockout] mice. The inflammatory cells can’t escape. Without this MMP2 enzyme, the cells come in but they have no way of leaving. The pulmonary escape routes are very much blocked off. On subsequent challenges with antigens which normal mice have very little difficulty handling these now-asthmatic animals begin to drown. And they die of asphyxiation literally drowning. They can’t breathe.”

Corry, at Baylor College of Medicine in Houston, is first author of an article in the April 2002 issue of Nature Immunology. Its title: “Decreased allergic lung inflammatory cell egression and increased susceptibility to asphyxiation in MMP2 deficiency.”

“Our findings,” he told BioWorld Today, “were that this MMP2 is a protease an enzyme. We find it in an experimental model of asthma. MMP2 is an enzyme that chops up proteins, and is strongly activated in our experimental asthma mouse model. Besides that protease,” he continued, “we also used an inhibitor in normal wild-type mice that knocked out a bunch of matrix metalloproteinases. We got a consistent result, one that we strongly suspect is relevant for human asthma as well.”

Asthma: Death By Asphyxiation

“Death from asthma in humans,” Corry noted, “is a rare event. “At the most, about 5,000 people die each year of it in the U.S. But when people die of asthma, they’re dying of asphyxiation.”

Corry and his co-authors, he recounted, “used two strains of mice. One was highly susceptible to the asthma phenotype and one was not. They were rather divergent strains in terms of their function in this asthma model. In order to investigate the functions of MMP2 in the wild-type strains, we used an inhibitor of MMP2. Blocking the enzyme with this inhibitor produced exactly the same result as with MMP2 knockout animals.

“To challenge the mice with asthma-triggering allergens,” he went on, “we used two different antigens, which we gave the mice by spraying into their nostrils. One that is most commonly employed in experimental asthma models is chicken-egg ovalbumin. The second antigen, which is more relevant to human disease, is derived from the fungus Aspergillus fumigatus, a major fungal pathogen. We knew the mice died of asphyxiation, because we could protect them by administering oxygen for 10 minutes before and after challenge. That reduced mortality to 20 percent in MMP-minus mice and zero in wild-type animals. That key insight, too, was relevant to human asthma.”

Turning to the underlying mechanism, Corry explained, “After cells come into any region of the body, as part of an inflammation, they have to leave, as part of the normal process of resolving the inflammation. Once the inflammatory insult has resolved, then the body will have to do something to turn it off. Those exit mechanisms are more mysterious than the ones that initiate the inflammation,” he pointed out. “This provided us with insight into the resolution of the asthmatic inflammation. MMP2 is a very important part of that resolution process. So the way this process appears to work is that in order for these eosinophils or other inflammatory cells relevant to asthma to come into the lung, they must be induced to enter in response to a variety of molecular signals.

“The most important of these,” Corry said, “is the signal carried by chemokines a group of molecules expressed in sites of inflammation. Their presence is detected by chemokine receptors, which are present on inflammatory cells. They will migrate into the organ the lung in this case according to the concentration gradient of these chemokines. These move from low to high concentration. It turns out they follow the same process to get out. Once cells have come into the lung and done their duty, whatever it is, as part of their inflammatory program, they then leave the lung, according to a second chemokine gradient.

“In the lung,” Corry went on, “that gradient is established across the airway wall. So cells come into the blood stream, and cross the endothelium of the blood vessels to get into the lung. But to get out again, once in the airway, they are coughed up in mucus and then swallowed. You literally digest away your lung inflammation. We determined that MMP2 is required to establish this chemokine gradient, which is necessary to get the cells out of the middle of the lung and into the airway, where they can be effectively cleared.”

TH2: Prime Asthma Perpetrator

“In this asthma model,” Corry observed, “there’s one particular leukocyte, called a T-helper cell type 2 (T_H2), that is absolutely required for the experimental asthma phenotype. And it’s the T-helper cells type 2 that are responsible for asthma. To cause disease, first they have to come into the lungs. The chemokines call them in. Once in a while that T_H2 leukocyte reactivates and makes a large series of interleukin-type cytokines like IL4, 5, 6, 9, 13 kind of a numbers game. The bottom line is that IL-13 is the most important. For one thing, T_H2 induces the chemokines that are required to get other inflammatory cells into the lung. IL-13 acts on the airway to induce mucus oversecretion, and a physiological phenomenon called airway hyperresponsiveness. These are two features of airway obstruction that are thought to be relevant to human asthma.”