© 2003 American Thoracic Society
Do low exhaled condensate nh4+ concentrations in asthma reflect reduced pulmonary production?To the Editor:Hunt and colleagues (1) recently reported that concentrations of NH4+ in exhaled condensates are reduced in patients with acute asthma and suggested that this is due to impaired glutaminase activity in the epithelial cells of these patients. However, three alternative explanations must be considered: (1) Much of the NH4+ that is found in condensates is derived from the mouth (salivary concentrations are approximately 100 times and condensate concentrations approximately 10 times those in the blood) and it is transported to the condenser as gaseous NH3 (2). The remarkable 1,000-fold variability of NH4+ concentrations found by Hunt and colleagues in condensates of normal subjects (1) could reflect differences in oral flora with urease activity and the volume of saliva present in the mouth, which can vary considerably during the course of a day. Low NH4+ concentrations in asthmatic condensates may be related to reduced volumes of saliva in the mouth caused by such factors as dehydration, catecholamine levels, and panting. (2) Decreased NH4+ recovery in asthmatic condensates could also reflect low end-tidal CO2 partial pressures. These low concentrations are due to hyperventilation and increased dead space, which are frequently encountered in patients with acute asthma. Low end-tidal CO2 would tend to alkalinize droplets and reduce NH4+ trapping in the condensers (2). Although the pH of the condensate was reduced in asthma, this may be misleading, because Hunt and colleagues purged CO2 from their samples. (3) Rapid shallow breaths could also result in increased trapping of NH4+ generated in the mouth and lungs by droplets lining the tubing that connects the patients to the condensers (2). Although the authors were able to document NH4+ production by epithelial cells in culture wells over the course of several days, it is difficult to extrapolate these results to in vivo conditions. Most NH4+ formation occurs in the kidney, gastrointestinal tract, and muscles (during exercise) (3). Net production by the lungs has not been described (3) and it might be difficult to document because of inhalation of NH3 from the mouth, the arterial–venous pH gradient, and large blood flow. Because the lungs are so well perfused and ventilated, significant local gradients are unlikely, and most of the NH3 and NH4+ in the pulmonary secretions are probably delivered there from other organs by the pulmonary and bronchial circulations.
Medical College of Wisconsin Milwaukee, Wisconsin REFERENCES
From the Authors:We have published our agreement (1, 2) with Dr. Effros that (1) there is ammonia (NH3) produced in the mouth as well as in the lower airways, and (2) there are buffers relevant to breath condensate pH yet to be identified. We appreciate the thought that he has put into this topic.To test the hypothesis that asthmatic hyperventilation might cause breath condensate pH changes requires a very simple experiment in humans. We performed this experiment (3). Hyperventilation affects neither breath condensate pH nor NH3 levels. Although Dr. Effros' theory is intriguing, it simply does not square with readily measurable empiric data. Low pH is a robust marker for airways inflammation (4, 5). It is reproducible not only within our group but between groups (1, 3–5). It reflects globally the solubilities, pKa, and titratable acidity of upper and lower airway buffers (1–4). On the other hand, oral NH3 (which has a nonphysiological pKa) does not substantially affect breath condensate pH: experimentally, neither changing the oral NH3/NH4+ concentration nor changing the oral pH have a significant effect on our breath condensate pH values. The lower airways produce NH3—resulting in concentrations of approximately 10-4 µM—in part as a result of epithelial glutaminase activity (1–3). Concentrations of NH3/NH4+ are in the range of 50 µM in the breath condensate of control subjects intubated for elective surgery (3). Decreased NH3 production is necessary, but is not sufficient, to explain low breath condensate pH (1). Breath condensate proton measurement, unlike the measurement of other solutes (6), is (1) highly reproducible, and (2) informative with respect to disease activity. That is to say, it is both reliable and useful. We agree that in vitro models involving two or three buffer systems studied in nonphysiological concentrations (6) have little role in interpreting breath condensate values in vivo. The complexity of the organic and inorganic chemistry prohibits one or two variables from being interpreted in isolation. Also, breath condensate collection systems need to be efficient. It is difficult to study the effects of subtle variations in technique using collection systems that take 15 minutes or longer and tend to collect variable fractions of saliva (6). We would like to thank Dr. Effros for his theoretical constructs; indeed, his thought processes have been very similar to ours. The theories just need to be continuously adjusted to fit the reality of data generated in physiologically relevant experiments.
University of Virginia School of Medicine Charlottesville, Virginia REFERENCES
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