Small Airway and Alveolar Tissue Changes in Nocturnal Asthma

RICHARD J. MARTIN

National Jewish Medical and Research Center, Denver, Colorado

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Investigation of airway events in nocturnal asthma provides a model for relating changes in physiology and inflammation in a naturally occurring situation, thereby giving insight into the relationship between structure and function in asthma.

The Mechanisms Causing Nocturnal Asthma

A brief overview of nocturnal asthma is seen in Figure 1. There are many complex interactions that produce the nocturnal worsening of asthma (1). Not only does lung function decrease at night, but bronchial hyperreactivity increases from day to night. These changes have been related to the normally occurring circadian changes in cortisol levels at night. The decrement in cortisol may lead to downregulation of the ₂-adrenergic receptors (2). In nocturnal asthma patients there appears to be significantly expressed genetic polymorphism (Gly16) that is linked to downregulation of the ₂ receptor (3). Epinephrine also has a circadian variation, with lower levels occurring during the night. Therefore, this endogenous bronchodilator is not as available at the time of need in nocturnal asthma. In addition, vagal tone is also increased at night, which promotes bronchoconstriction. Part of the nocturnal bronchoconstriction in asthma can be prevented by blockade of parasympathetic tone (4, 5). There is also accumulating evidence that the inflammatory airway response is also increased at night (6). The basis for this change is not fully understood; whether it is a release of the "brakes," with decreasing cortisol and epinephrine and/or other factors, needs to be established. Clearly, then, a combination of factors may set in motion the asthmatic response at night.

View larger version (17K): [in this window] [in a new window]   Figure 1.   Potential mechanisms that contribute to the worsening of asthma at night. Epi = epinephrine; temp = temperature. Reproduced from Reference 1 with permission.

Lower airway resistance and nocturnal asthma. Studying pulmonary physiology during sleep is difficult, but it can be accomplished. By measuring breath-by-breath airway resistance (Figure 2) during sleep and recumbent wakefulness overnight, we can learn about the role sleep plays in nocturnal asthma (9). There is a slow progressive increase in airway resistance during the night in the awake state. This increase is more profound during sleep. Thus, there is a circadian rhythm in lung function independent of sleep, but factors associated with sleep itself have a significant additional effect on the worsening of asthma at night.

View larger version (17K): [in this window] [in a new window]   Figure 2.   Lower airway resistance (Rla) in asthmatic subjects, from midnight to 6:00 A.M., when awake (dashed line) or asleep (solid line). Reproduced from Reference 9 with permission.

Bronchial hyperreactivity and nocturnal asthma. A control group (defined by a fall in FEV₁ of < 10% overnight) and a nocturnal asthma group (overnight FEV₁ fall > 20%) were challenged with methacholine at 4:00 P.M. and 4:00 A.M. (10). Both groups had an increased responsivity from 4:00 P.M. to 4:00 A.M. (Figure 3). The control group had minimal falls in FEV₁, yet had about a twofold increase in bronchial reactivity from day to night. The nocturnal asthma group started with a slightly higher reactivity than the nonnocturnal asthma group, but had an approximately eightfold increase in reactivity from day to night.

View larger version (16K): [in this window] [in a new window]   Figure 3.   The circadian variation in bronchial reactivity between 4:00 P.M. and 4:00 A.M. in control and nocturnal asthmatics (horizontal lines represent mean values). Constructed from data in Reference 10.

Lung-volume changes and nocturnal asthma. Unexpected lung-volume changes occur at night in asthmatic patients. Using a supine body plethysmograph, we have shown in normal volunteers (11) that the functional residual capacity (FRC) falls from wakefulness to sleep and is at its lowest during rapid eye movement (REM) sleep (Figure 4). Asthmatic patients exhibit airway hyperinflation compared with normal subjects during daytime. However, during sleep they have marked decreases in FRC, and during REM sleep the FRC actually decreases to the volume observed in normal subjects. Thus, during sleep with decreasing FEV₁, asthmatics do not increase FRC, but rather have decreases in this value. If lung volume falls during sleep in people with asthma, then this change could contribute to the sleep-related increase in airway resistance. This would hold true unless there is uncoupling of the parenchyma and the airways. Using a continuous negative-pressure system around the thorax to maintain FRC during sleep, no changes from baseline values were found in overnight FEV₁ or bronchial hyperresponsiveness (12). This finding suggests that the volume-resistance relationship is lost in nocturnal asthma during sleep.

View larger version (8K): [in this window] [in a new window]   Figure 4.   The FRC of normal (solid line) and asthmatic (dashed line) subjects. *p < 0.05 wakefulness and REM sleep versus all sleep stages in the patients with asthma, wakefulness versus other sleep stages in normal subjects; p < 0.05, patients with asthma versus normal subjects. Reproduced from Reference 11 with permission.

Peripheral airway resistance and nocturnal asthma. Daytime studies by Wagner and colleagues have suggested that the more peripheral airways are involved in asthma (13). Comparing normal control subjects to an asymptomatic asthmatic group with similar spirometric values, the asthmatic group had markedly increased peripheral airway resistance, as measured with a wedged bronchoscope. This sensitive measurement is made by inserting a double-lumen catheter through the bronchoscope. One channel is used to give increasing flow rates, and the other channel measures changes in pressure due to the increasing flow. As the flow is increased in normal subjects there is little to no change in pressure; i.e., resistance remains constant. In patients with asthma, marked pressure changes can be measured. This study and the others mentioned suggest that inflammation in the alveolar tissue area may play an important role in asthma.

Airway inflammation and nocturnal asthma. The next step in our series of studies was to evaluate the degree of alveolar and airway inflammation in nocturnal asthma by obtaining and analyzing transbronchial and endobronchial biopsies at 4:00 P.M. and 4:00 A.M. from patients with asthma (7). At 4:00 P.M. there was a slight, but insignificant, increase in eosinophils in the alveolar tissue area compared to the proximal airways in both the asthma control group and the nocturnal asthma group (Figure 5). At 4:00 A.M., there was a marked and significant increase in alveolar tissue eosinophils in the nocturnal asthma group. Additionally, the overnight decrease in lung function correlated with the number of alveolar eosinophils (r = 0.54, p = 0.03) but not with the number of proximal airway eosinophils (r = 0.16, p = 0.59). This again suggests that the nocturnal inflammatory response in the distal units may cause an uncoupling of the parenchyma and airways.

View larger version (12K): [in this window] [in a new window]   Figure 5.   The number per volume (Nv) of eosinophils (eos) in the nocturnal asthma (NA) and nonnocturnal asthma (NNA) groups in the endobronchial (airway tissue, EBBX) and transbronchial (alveolar tissue, TBBX) biopsies at 4:00 A.M. and 4:00 P.M. Values are expressed as medians with the 25-75 interquartile range in parentheses above each bar. *p  0.05. Reproduced from Reference 7 with permission.

Conclusion

The studies reported here suggest that alveolar inflammation is a feature of nocturnal asthma. Changes in inflammation at this site and in the small airways could significantly contribute to this aspect of the disease process. The persistence of inflammation at this site in patients with nocturnal asthma treated with inhaled steroids raises the speculation that inhaled anti-inflammatory medications may not be treating the entire pathologic area of involvement in asthma. That is, until better methods to deliver the inhaled medication to the very terminal airways are developed, these areas could continue to hinder our ability to truly capture the inflammatory process in asthma. The development of improved delivery systems, enabling targeted drug delivery to the small airways and alveolar spaces, will enable inflammation to be treated more effectively.

	Footnotes

Correspondence and requests for reprints should be addressed to Richard J. Martin, M.D., National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: martinr{at}njc.org

	References

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13. Wagner, E. M., M. C. Liu, G. G. Weinmann, S. Permutt, and E. R. Bleecker. 1990. Peripheral lung resistance in normals and asthmatic subjects. Am. Rev. Respir. Dis. 141: 584-588 [Medline].