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Running is good!

Aerobic exercise fights inflammation and stiffening of the lungs in respiratory diseases such as asthma and pneumonia

Mini-gym: on the adapted treadmill, several mice can run at the same time

EDUARDO CESARMini-gym: on the adapted treadmill, several mice can run at the same time EDUARDO CESAR

The relatively old warning to asthmatics to avoid participating in sports seems to be based on a misunderstanding, according to the work of Rodolfo de Paula Vieira of the São Paulo based Nove de Julho University (Uninove). Since completing his doctorate in physical education at the University of São Paulo School of Medicine (FMUSP), his research has focused on probing and demonstrating how aerobic exercise fights the harmful effects of respiratory diseases. “It’s important for the exercise to be moderate to produce the beneficial effects without triggering asthma attacks,” he says. “The problem is that it’s difficult to control the intensity of the effort of children in gym class.”

Vieira began his doctoral studies in 2004 intending to focus on the effects of exercise on asthma, with two USP professors, Dr. Marisa Dolhnikoff and Celso Carvalho, a physiotherapist, serving as his advisors. He suffered his first setback just one month later, when an article by the American immunologist group led by Lisa Schwiebert of the University of Alabama at Birmingham was published in the Journal of Immunology. The article showed that exercise could reduce the inflammatory processes in asthmatic mice. But Vieira was undeterred and went on to further describe these effects, showing in an article published in 2007 in the American Journal of Respiratory and Critical Care Medicine, that, in addition to the anti-inflammatory effects on lung tissue, exercise can also combat the fibrosis typical of asthma. “Unresolved inflammation leads to thickening of the airways, which is a progressive and irreversible process,” he says. This fibrosis makes the lungs less flexible and reduces gas exchange—effects that can last a lifetime, even if attacks are controlled.

In recent years, in part during his post-doctorate at the University of Freiburg, Germany, Vieira has shown the beneficial effects of exercise on respiratory diseases such as asthma, chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome and pneumonia as well as in situations that aggravate the respiratory passages, such as exposure to air pollution and cigarette smoke. Much of the work was done using mice as a model, but this is likely to change soon.

Box connected to a tube holding a cigarette simulates the effects in smokers

EDUARDO CESARBox connected to a tube holding a cigarette simulates the effects in smokersEDUARDO CESAR

“In early 2015 we will open a physical assessment and pulmonary rehabilitation center open to the public,” says Vieira, showing off a room with 15 treadmills—on loan from the university—and an exercise bicycle. “We will also have strength training equipment and the infrastructure to collect blood, saliva and sputum induced for analysis.” All of this will be housed in a large space on the Uninove campus, located on Rua Vergueiro in the Liberdade neighborhood of São Paulo, a huge building through which 35,000 students pass each day. Despite a limited tradition of academic research, the university gave in and is renovating the areas required to set up Vieira’s laboratory, thanks to funding for the project from FAPESP’s Young Investigators Awards Program, which began this year. The conversation on which this report is based took place amidst newly installed equipment. “This centrifuge was delivered last week,” said Vieira, as he taught students how to operate it. By the end of the year he expects to receive all the equipment already on order and be ready to recruit human volunteers to pitch in and donate sputum and blood. “The idea is for us to evaluate not only the inflammatory and anti-inflammatory factors in the respiratory tract, but also systemic inflammation in the blood through use of the flow cytometry technique,” said Vieira, referring to the main laboratory device obtained through FAPESP’s Multi-User Equipment Program.

So far, the studies on rodents have allowed them to proceed with mapping how the effects of exercise reach the lungs. In an article published in June 2014 in the International Journal of Sports Medicine, he measured the number of proteins with anti-inflammatory action (interleukin-10) and inflammatory action (interleukin 4, 5 and 13) in the liquid obtained by bronchial lavage and in the blood of mice subjected to an exercise regime on adapted treadmills, with or without using ovalbumin, which induces a condition similar to asthma in rodents. The results show that asthma increases the concentration of inflammatory factors, which is reduced by a regimen of daily running. “Exercise activates the skeletal muscles, the regulatory T cells and bronchial epithelium, leading to the production of interleukin-10, which enters the bloodstream and reaches the lungs,” says Vieira. Much of this protein is in the systemic circulation and can fight inflammation where needed, but a fraction goes into the lungs and adds to what is produced there.

But the most noteworthy feature of the study was to indicate that increasing or reducing the production of certain substances with aerobic exercise inhibits activation of leukocytes, the cells of the immune system involved in the inflammatory process, in the lungs. In addition to the interleukins, exercise also inhibits the action of other protagonists in this story: several growth factors, proteins that act on cell proliferation and differentiation and are believed to be the main mediators of airway changes, such as fibrosis.

The beneficial effect of exercise is also evident in healthy people exposed to the harmful effects of air pollution, such as runners who train near highways. In the case of the experiment, conducted in partnership with Dr. Marisa Dolhnikoff and Paulo Saldiva of the School of Medicine’s Experimental Air Pollution Laboratory, the athletes were mice running on treadmills. After running for 10 minutes, each received one drop in each nostril of a concentrated solution of particles emitted from the exhaust pipes of diesel vehicles. They returned to running, simulating a moderate aerobic exercise session. “We were surprised to see that exercise protects the lungs,” says Vieira, who expected to find a layer of these particles deposited in the respiratory system of the rodents. “Now we need to investigate how this happens.” He thinks that the lung epithelium (lining) can become more efficient in removing the pollutant, with its microscopic hair working like the bristles of tireless brooms. Whatever the mechanism, the result brings a note of optimism for breathless cyclists who jostle for space on the streets with cars spewing exhaust fumes, but he still needs to wait to see if the experiments with rodents reflect human reality.

Other particulates that often cause extensive damage are those inhaled by smokers, and they can be an important factor in the development of emphysema and COPD. In collaboration with the group led by the USP Medical School’s Milton Martins, Vieira participated in a study in which mice, over a period of 24 weeks, were placed in chambers connected to a tube holding a lit cigarette; the rodents were exposed to the tip end and inhaled its smoke, not unlike the secondary smoke typically inhaled by those who live with smokers. The results, published in 2012 in the European Respiratory Journal, showed that a training regime on a treadmill five days a week significantly reduced the production of substances responsible for oxidative stress, while at the same time increased the level of antioxidant enzymes. The balance was protection against emphysema in these rodents. The results suggest that the protection may also be true for COPD in humans. Mice continue to smoke in the Uninove laboratory, so that more results are likely to emerge in the coming years.

Vieira’s efforts have been recognized by both an extensive network of collaborations and a large number of publications, despite the fact that the laboratory is a work-in-progress. His group won the most awards at the European Respiratory Society Congress, which was held in September 2014 in Munich, Germany. It received four awards. One of them was for showing that physical exercise protects against pneumonia caused by the bacterium Pseudomonas aeruginosa, the main culprit of opportunistic infections in hospitals and deaths in intensive care units. “The inflammation was 70% lower in the acute phase of pneumonia,” he says. “It was the first work by our group in respiratory infection,” he says, celebrating his wonderful reception at the international meeting, which brought together about 22,000 experts.

With the start of testing with human volunteers, partnerships with hospitals and clinical care at Uninove, Vieira promises much that will be newsworthy in the coming years. For now, the message to asthmatics is: exercise regularly under supervision, but don’t overdo it!

1. Role of SOCS-JAK-STAT signaling in the anti-inflammatory effects of aerobic training in experimental models of asthma and asthmatic individuals (No. 2012/15165-2); Grant mechanism Young Investigators Awards; Principal investigator Rodolfo de Paula Vieira (Uninove); Investment R$1,131,587.47 (FAPESP).
2. Multi-User Equipment granted in process 2012/15165-2: Accuri Flow Cytometer (No. 2014/07171-8); Grant mechanism Multi-User Equipment Program; Principal investigator Rodolfo de Paula Vieira (Uninove); Investment R$161,798.40 (FAPESP).

Scientific articles
VIEIRA, R. P. et al. Exercise deactivates leukocytes in asthma. International Journal of Sports Medicine. v. 35, n. 7, p. 629-35. jun 2014.
VIEIRA, R. P. et al. Anti-inflammatory effects of aerobic exercise in mice exposed to air pollution. Medicine & Science in Sports & Exercise. v. 44, n. 7, p. 1227–34. jul. 2012.
TOLEDO, A. C. et al. Aerobic exercise attenuates pulmonary injury induced by exposure to cigarette smoke. European Respiratory Journal. v. 39, n. 2, p. 254–64. feb. 2012.