CHARLOTTESVILLE, VA (March 13) - In a potentially pivotal finding for physicians who treat asthma and medical researchers who study the disease, a study in the March issue of the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine reports that acutely ill asthmatics have a dramatic but reversible degree of acidity in the water expired from their lungs. This surprising observation may point the way toward new, low-toxicity therapies aimed at restoring the natural pH balance of the airway, and also highlights the importance of nitric oxide-containing compounds that help to keep the airway open in health, but are broken down in acute asthma, according to the investigators.
The investigators found a low pH in the expired air of acutely ill asthmatics. The pH is a measurement of the acidity or alkalinity of solutions. A pH below 7 is considered acid, and a pH above 7 is alkaline. Mean pH values were 7.65 in control subjects and 5.2 in asthmatics. Further, this acidity normalized with glucocorticoid treatment.
John F. Hunt, M.D., of the University of Virginia Health System, and six associates, point out that airway pH has never before been studied in acute asthma, and speculate, "Šairway pH may be an important determinant of expired nitric oxide concentration and airway inflammationŠ" and suggest that, "Šthe regulation of airway pH has a previously unsuspected role in asthma pathophysiology."
The researchers collected data from 22 patients with acute asthma (mean age 19.5 -- 10 males), 19 controls, and 12 subjects with stable asthma (mean age 21.5 -- 6 males). Patients hospitalized for acute asthma had low pH values, which showed steady to normal values during anti-inflammatory therapy. Measurements were highly stable and reproducible. The researchers extensively considered non-pulmonary causes for airway vapor acidification and excluded salivary, nasal and gastric contamination from their samples.
The researchers indicate that this acidity may account for much of the exhaled nitric oxide that has been associated with the airway inflammation seen in asthma. Through the latter half of the 1990s, nitric oxide production in the asthmatic airway has been increasingly accepted as either a compensatory mechanism that counters airway hyper-reactivity or as directly contributing to the inflammation. As recently as December, the American Thoracic Society published its official recommendations for standardized procedures for measurement of exhaled nitric oxide in adults and children with asthma.
In an editorial accompanying the study, Jonathan S. Stamler, M.D., and Harvey E. Marshall, M.D., of Duke University Medical Center, explain that "the lung, like most other tissues, does not handle acid well."
"Remarkably, lowering the airway pH of airway linings into the asthmatic range produces bronchospasm, impairs ciliary motility, increases mucus viscosity, damages the epithelium and causes eosinophil spillage of bronchoconstrictor and pro-inflammatory substances." Drs. Stamler and Marshall state, "That is, airway acidification recapitulates many of the classical manifestations of reactive airway disease."
As a potentially pivotal discovery in the field of asthma research, these early observations raise new questions for asthma researchers around the world, according to Dr. Stamler. It calls into question the current practice of measuring nitric oxide in asthmatics, he said. "Perhaps it's not a marker of inflammation, but a marker of the pH level. In that case, we could be more effectively monitoring the pH level directly." A non-invasive pH monitor to measure the acuity of asthma would have great implications, especially for children. If the pH level was found to be a predictor of an asthma attack, the implications are greater still, Dr. Stamler remarked.
The study raises new challenges for asthma researchers. Among those outlined by Drs. Stamler and Marshall are: Is there an acid-based defect in asthmatics? How closely linked is acidification to inflammation of the airways? Is the fall in pH a consequence of inflammation or a cause of it? Does airway acidification occur in other obstructive lung diseases? And, on a cellular level, could the change in pH affect the life span of eosinophils?
Perhaps the ultimate question raised by this study is whether the acidosis demonstrated by Hunt and his colleagues can be corrected. If so, it would open the door to novel therapies for asthma. As Drs. Stamler and Marshall speculate, "Enter the era of antacid therapy of the lung."
Though the finding that the pH of expired air in acute asthma is novel and has the potential to have a major impact on asthma research, the researchers caution that their observations are preliminary. More studies will be needed to determine the cause for low pH in the expired air of patients with acute asthma, and to define more precisely the implications of this finding.
Other authors of the study include Kezhong Fang, Ph.D.; Rajesh Malik, M.D.; Ashley Snyder; Neil Malhotra, B.A.; Thomas A.E. Platts-Mills, M.D., Ph.D; and Benjamin Gaston, M.D. This study, conducted at the University of Virginia Health System, exemplifies the public and private partnerships that support basic and clinical research to improve the lives of people with lung disease. The researchers were supported by research grants from the Virginia Thoracic Society -- a chapter of the American Thoracic Society, the American Lung Association, the National Institutes of Health, and the University of Virginia Children's Medical Center.
Author Contact: Benjamin Gaston, M.D., University of Virginia Health System Department of Pediatrics, Phone: 804-924-1820; Fax: 804-243-6618.
Journal
American Journal of Respiratory and Critical Care Medicine