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
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 noctur-
nal worsening of asthma (1). Not only does lung function de-
crease 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 dec-
rement in cortisol may lead to downregulation of the b2-adre-
nergic receptors (2). In nocturnal asthma patients there ap-
pears to be significantly expressed genetic polymorphism (Gly16)
that is linked to downregulation of the b2 receptor (3). Epi-
nephrine also has a circadian variation, with lower levels oc-
curring during the night. Therefore, this endogenous bron-
chodilator 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 bron-
choconstriction in asthma can be prevented by blockade of
parasympathetic tone (4, 5). There is also accumulating evi-
dence that the inflammatory airway response is also increased
at night (6–8). The basis for this change is not fully under-
stood; whether it is a release of the “brakes,” with decreasing
cortisol and epinephrine and/or other factors, needs to be es-
tablished. Clearly, then, a combination of factors may set in
motion the asthmatic response at night.
Lower airway resistance and nocturnal asthma. Studying
pulmonary physiology during sleep is difficult, but it can be ac-
complished. 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 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,
Denver, CO 80206. E-mail: martinr@njc.org
Am J Respir Crit Care Med Vol 157. pp S188–S190, 1998
but had an approximately eightfold increase in reactivity from
day to night.
Lung-volume changes and nocturnal asthma. Unexpected
lung-volume changes occur at night in asthmatic patients. Us-
ing 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 de-
creases in FRC, and during REM sleep the FRC actually de-
creases to the volume observed in normal subjects. Thus, dur-
ing 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 resis-
tance. 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 over-
night FEV1 or bronchial hyperresponsiveness (12). This find-
ing suggests that the volume-resistance relationship is lost in
nocturnal asthma during sleep.
Peripheral airway resistance and nocturnal asthma. Day-
time studies by Wagner and colleagues have suggested that
the more peripheral airways are involved in asthma (13). Com-
paring 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 bron-
choscope. 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
Figure 1. Potential mechanisms that contribute to the worsening
of asthma at night. Epi 5 epinephrine; temp 5 temperature. Re-
produced from Reference 1 with permission.
Martin: Small Airway Changes in Nocturnal Asthma
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.
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 im-
portant 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 signifi-
cant 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 5 20.54, p 5 0.03) but not with the number of proximal air-
Figure 3. The circadian variation in bronchial reactivity between
4:00 P.M. and 4:00 A.M. in control and nocturnal asthmatics (hori-
zontal lines represent mean values). Constructed from data in Ref-
erence 10.
S189
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.
way eosinophils (r 5 20.16, p 5 0.59). This again suggests that
the nocturnal inflammatory response in the distal units may
cause an uncoupling of the parenchyma and airways.
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 inflam-
mation 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 patho-
logic area of involvement in asthma. That is, until better methods
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-
lar tissue, TBBX) biopsies at 4:00 A.M. and 4:00 P.M. Values are ex-
pressed as medians with the 25–75 interquartile range in paren-
theses above each bar. *†‡p < 0.05. Reproduced from Reference 7
with permission.
S190 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE
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 de-
velopment of improved delivery systems, enabling targeted
drug delivery to the small airways and alveolar spaces, will en-
able inflammation to be treated more effectively.
References
1. Martin, R. J. 1993. Nocturnal asthma: an overview. In R. J. Martin, edi-
tor. Nocturnal Asthma: Mechanisms and Treatment. Futura Publish-
ing Co., Inc., Mount Kisco, NY. 71–115.
2. Szefler, S. J., R. Ando, L. C. Cicutto, W. Surs, M. R. Hill, and R. J. Mar-
tin. 1991. Plasma histamine, ephinephrine, cortisol, and leukocyte beta-
adrenergic receptors in nocturnal asthma. Clin. Pharmacol. Ther. 49:59–
68.
3. Turki, J., J. Pak, S. A. Green, R. J. Martin, and S. B. Liggett. 1995. Ge-
netic polymorphisms of the beta 2-adrenergic receptor in nocturnal
and nonnocturnal asthma: evidence that Gly16 correlates with the
nocturnal phenotype. J. Clin. Invest. 95:1635–1641.
4. Kellenbach, J. M., T. Webster, R. Dowdeswell, S. G. Reinach, R. N.
Millar, and S. Zwi. 1985. Reflex heart rate control in asthma: evidence
of parasympathetic overactivity. Chest 87:644–648.
5. Morrison, J. F., S. B. Pearson, and H. G. Dean. 1988. Parasympathetic
VOL 157 1998
nervous system in nocturnal asthma. B.M.J. (Clin. Res. Ed.) 296:1427–
1429.
6. Martin, R. J., L. C. Cicutto, H. R. Smith, R. D. Ballard, and S. J. Szefler.
1991. Airways inflammation in nocturnal asthma. Am. Rev. Respir. Dis.
143:351–357.
7. Kraft, M., R. Djukanovic, S. Wilson, S. T. Holgate, and R. J. Martin.
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-
tabolism of oxygen radicals in nocturnal asthma. Am. Rev. Respir. Dis.
146:905–911.
9. Ballard, R. D., M. C. Saathoff, D. K. Patel, P. L. Kelly, and R. J. Martin.
1989. Effect of sleep on nocturnal bronchoconstriction and ventilatory
patterns in asthmatics. J. Appl. Physiol. 67:243–249.
10. Martin, R. J., L. C. Cicutto, and R. D. Ballard. 1990. Factors related to
the nocturnal worsening of asthma. Am. Rev. Respir. Dis. 141:33–38.
11. Ballard, R. D., C. G. Irvin, R. J. Martin, J. Pak, R. Pandey, and D. P.
White. 1990. Influence of sleep on lung volume in asthmatic patients
and normal subjects. J. Appl. Physiol. 68:2034–2041.
12. Martin, R. J., J. Pak, and C. G. Irvin. 1993. The effect of lung volume
maintenance during sleep in nocturnal asthma. J. Appl. Physiol. 75: 1467–
1470.
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.