Key Point:

Airway hyperreactivity in some asthma patients may be caused by elevated arginase activity, which results in decreased arginine and nitric oxide levels.

OAKLAND, CALIF—The role of inflammation in the pathogenesis of asthma is well accepted and often attributed to T_H2 cytokines. Nitric oxide, which is produced from arginine, is another inflammatory mediator. Working on the supposition that asthma is a disease of decreased nitric oxide bioavailability, researchers measured arginase activity in the blood of asthma patients, as well as levels of nitric oxide in exhaled breath. They found that reduced arginine bioavailability concomitant with increased arginase activity may contribute to hyperreactive airways in asthma.¹

Twenty-six patients (mean age, 14) with asthma who were in various stages of symptom exacerbation were studied. Exhaled breath samples were collected from 22 patients and tested for nitric oxide. Blood samples were obtained from all patients and tested for levels of amino acids, arginase activity, and nitric oxide metabolites. Four of 16 patients who were admitted to the hospital because of asthma symptoms had daily blood samples collected and tested. In addition, 15 nonasthmatic children served as a control group.

ARGININE DECREASED, ARGINASE INCREASED

Patients who were experiencing an acute asthma exacerbation had roughly a 50% decrease in plasma levels of arginine. The relative availability of arginine was also significantly lower in patients than in the control group.

On the other hand, serum arginase activity was significantly increased among patients versus controls. As shown in other studies, levels of exhaled nitric oxide were also significantly higher in asthma patients, regardless of the level of decline in plasma arginine levels.

In the four patients who were hospitalized, plasma arginine levels were low on the day of admission and increased steadily until discharge. However, there were no consistent changes in relative arginine availability. According to serial arginase measurements taken in two patients, arginase levels decreased into the normal range by the time of discharge.

Reduced arginine availability may contribute to lung injury by enabling the formation of superoxide and cytotoxic reactive nitric oxide species. Proline and ornithine, the downstream products of arginase activity, promote collagen synthesis and cell proliferation—two processes that occur in the thickening of airway walls and in airway remodeling.

Claudia R. Morris, MD, Attending Physician and Clinical Scientist in the Department of Emergency Medicine at the Children’s Hospital and Research Center in Oakland, California, and colleagues examined additional patient data and found that patients who returned to their baseline asthma symptoms still had elevated arginase levels, low arginine levels, and an abnormally low arginine/ornithine ratio. “Persistent aberrations in this pathway may reflect chronic inflammation or poor control,” she said.

“The reduced bioavailability of arginine may play an important role in both the incidence and duration of asthmatic episodes,” Dr. Morris continued, “and we believe that elevated arginase activity is likely one step in a cascade of events that contribute to both the acute and chronic symptoms of asthma.”

Relative and absolute arginine availability is decreased in patients during the course of an acute asthma exacerbation. Decreased arginine levels may reflect depletion in the substrate due to the increased demand for nitric oxide in order to maintain bronchodilator tone while compensating for increased nitric oxide consumption during oxidative stress and inflammation, in addition to elevated arginase activity.

POTENTIAL TARGET FOR TREATMENT

The goal of therapy would be to maximize arginine and nitric oxide bioavailability, while shifting arginine metabolism away from ornithine-dependent pathways, said Dr. Morris. “Although arginase inhibitors have been developed that are effective in vitro, there is very little information on their effects in animals and none on their effects in humans,” she explained. Dr. Morris noted the answer might lie with combination therapy that uses both an arginase inhibitor and arginine supplementation.

—Gale Jurasek

Reference
1. Morris CR, Poljakovic M, Lavrisha L, et al. Decreased arginine bioavailability and increased serum arginase activity in asthma. Am J Respir Crit Care Med. 2004;170:148-153.

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