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Small Airway and Alveolar Tissue Changes

in Nocturnal Asthma
RICHARD J. MARTIN
National Jewish Medical and Research Center, Denver, Colorado

Investigation of airway events in nocturnal asthma provides a but had an approximately eightfold increase in reactivity from
model for relating changes in physiology and inflammation in day to night.
a naturally occurring situation, thereby giving insight into the Lung-volume changes and nocturnal asthma. Unexpected
relationship between structure and function in asthma. lung-volume changes occur at night in asthmatic patients. Us-
ing a supine body plethysmograph, we have shown in normal
The Mechanisms Causing Nocturnal Asthma volunteers (11) that the functional residual capacity (FRC)
A brief overview of nocturnal asthma is seen in Figure 1. falls from wakefulness to sleep and is at its lowest during rapid
There are many complex interactions that produce the noctur- eye movement (REM) sleep (Figure 4). Asthmatic patients
nal worsening of asthma (1). Not only does lung function de- exhibit airway hyperinflation compared with normal subjects
crease at night, but bronchial hyperreactivity increases from during daytime. However, during sleep they have marked de-
day to night. These changes have been related to the normally creases in FRC, and during REM sleep the FRC actually de-
occurring circadian changes in cortisol levels at night. The dec- creases to the volume observed in normal subjects. Thus, dur-
rement in cortisol may lead to downregulation of the b2-adre- ing sleep with decreasing FEV1, asthmatics do not increase
nergic receptors (2). In nocturnal asthma patients there ap- FRC, but rather have decreases in this value. If lung volume
pears to be significantly expressed genetic polymorphism (Gly16) falls during sleep in people with asthma, then this change
that is linked to downregulation of the b2 receptor (3). Epi- could contribute to the sleep-related increase in airway resis-
nephrine also has a circadian variation, with lower levels oc- tance. This would hold true unless there is uncoupling of the
curring during the night. Therefore, this endogenous bron- parenchyma and the airways. Using a continuous negative-
chodilator is not as available at the time of need in nocturnal pressure system around the thorax to maintain FRC during
asthma. In addition, vagal tone is also increased at night, which sleep, no changes from baseline values were found in over-
promotes bronchoconstriction. Part of the nocturnal bron- night FEV1 or bronchial hyperresponsiveness (12). This find-
choconstriction in asthma can be prevented by blockade of ing suggests that the volume-resistance relationship is lost in
parasympathetic tone (4, 5). There is also accumulating evi- nocturnal asthma during sleep.
dence that the inflammatory airway response is also increased Peripheral airway resistance and nocturnal asthma. Day-
at night (6–8). The basis for this change is not fully under- time studies by Wagner and colleagues have suggested that
stood; whether it is a release of the “brakes,” with decreasing the more peripheral airways are involved in asthma (13). Com-
cortisol and epinephrine and/or other factors, needs to be es- paring normal control subjects to an asymptomatic asthmatic
tablished. Clearly, then, a combination of factors may set in group with similar spirometric values, the asthmatic group had
motion the asthmatic response at night. markedly increased peripheral airway resistance, as measured
Lower airway resistance and nocturnal asthma. Studying with a wedged bronchoscope. This sensitive measurement is
pulmonary physiology during sleep is difficult, but it can be ac- made by inserting a double-lumen catheter through the bron-
complished. By measuring breath-by-breath airway resistance choscope. One channel is used to give increasing flow rates,
(Figure 2) during sleep and recumbent wakefulness overnight, and the other channel measures changes in pressure due to the
we can learn about the role sleep plays in nocturnal asthma increasing flow. As the flow is increased in normal subjects
(9). There is a slow progressive increase in airway resistance there is little to no change in pressure; i.e., resistance remains
during the night in the awake state. This increase is more pro-
found 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 worsen-
ing of asthma at night.
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,

Correspondence and requests for reprints should be addressed to Richard J. Mar-


tin, M.D., National Jewish Medical and Research Center, 1400 Jackson Street, Figure 1. Potential mechanisms that contribute to the worsening
Denver, CO 80206. E-mail: martinr@njc.org of asthma at night. Epi 5 epinephrine; temp 5 temperature. Re-
Am J Respir Crit Care Med Vol 157. pp S188–S190, 1998 produced from Reference 1 with permission.
Martin: Small Airway Changes in Nocturnal Asthma S189

Figure 2. Lower airway resistance (Rla) in asthmatic subjects, from


midnight to 6:00 A.M., when awake (dashed line) or asleep (solid Figure 4. The FRC of normal (solid line) and asthmatic (dashed line)
line). Reproduced from Reference 9 with permission. 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
constant. In patients with asthma, marked pressure changes normal subjects. Reproduced from Reference 11 with permission.
can be measured. This study and the others mentioned suggest
that inflammation in the alveolar tissue area may play an im-
portant role in asthma. way eosinophils (r 5 20.16, p 5 0.59). This again suggests that
Airway inflammation and nocturnal asthma. The next step the nocturnal inflammatory response in the distal units may
in our series of studies was to evaluate the degree of alveolar cause an uncoupling of the parenchyma and airways.
and airway inflammation in nocturnal asthma by obtaining
and analyzing transbronchial and endobronchial biopsies at Conclusion
4:00 P.M. and 4:00 A.M. from patients with asthma (7). At 4:00 The studies reported here suggest that alveolar inflammation
P.M. there was a slight, but insignificant, increase in eosinophils is a feature of nocturnal asthma. Changes in inflammation at
in the alveolar tissue area compared to the proximal airways this site and in the small airways could significantly contribute
in both the asthma control group and the nocturnal asthma to this aspect of the disease process. The persistence of inflam-
group (Figure 5). At 4:00 A.M., there was a marked and signifi- mation at this site in patients with nocturnal asthma treated
cant increase in alveolar tissue eosinophils in the nocturnal with inhaled steroids raises the speculation that inhaled anti-
asthma group. Additionally, the overnight decrease in lung inflammatory medications may not be treating the entire patho-
function correlated with the number of alveolar eosinophils logic area of involvement in asthma. That is, until better methods
(r 5 20.54, p 5 0.03) but not with the number of proximal air-

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 (alveo-
Figure 3. The circadian variation in bronchial reactivity between lar tissue, TBBX) biopsies at 4:00 A.M. and 4:00 P.M. Values are ex-
4:00 P.M. and 4:00 A.M. in control and nocturnal asthmatics (hori- pressed as medians with the 25–75 interquartile range in paren-
zontal lines represent mean values). Constructed from data in Ref- theses above each bar. *†‡p < 0.05. Reproduced from Reference 7
erence 10. with permission.
S190 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 157 1998

to deliver the inhaled medication to the very terminal airways nervous system in nocturnal asthma. B.M.J. (Clin. Res. Ed.) 296:1427–
are developed, these areas could continue to hinder our ability 1429.
6. Martin, R. J., L. C. Cicutto, H. R. Smith, R. D. Ballard, and S. J. Szefler.
to truly capture the inflammatory process in asthma. The de-
1991. Airways inflammation in nocturnal asthma. Am. Rev. Respir. Dis.
velopment of improved delivery systems, enabling targeted 143:351–357.
drug delivery to the small airways and alveolar spaces, will en- 7. Kraft, M., R. Djukanovic, S. Wilson, S. T. Holgate, and R. J. Martin.
able inflammation to be treated more effectively. 1996. Alveolar tissue inflammation in asthma. Am. J. Respir. Crit. Care
Med. 154:1505–1510.
8. Jarjour, N. N., W. W. Busse, and W. J. Calhoun. 1992. Enhanced me-
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