Nitric oxide in the airways

Glenis Scadding

Purpose of review Introduction

This review briefly explains the basic facts about nitric oxide, Nitric oxide is a colourless, odourless gas. It acts as a final
which is entering clinical practice as a measure of lower transmitter in many body systems and shows evolutionary
airways inflammation and is likely also to be employed in conservation, being first found in the horseshoe crab, that
otorhinolaryngological practice. is, it has been utilized for some 500 million years. Nitric
Recent findings oxide is formed in vivo from arginine by three isoforms of
These include the validity of nasal nitric oxide in diagnosing the enzyme nitric oxide synthase. In the vascular system,
primary ciliary dyskinesia and in monitoring the response to brain and kidneys, these enzymes are constitutive, that is,
chronic rhinosinusitis therapy. The nasal nitric oxide value permanently active and are called cNOS. In the immune
combined with a humming manoeuvre, which increases the system, they are inducible (iNOS) and are switched on
passage of nitric oxide from the sinuses to the nose if the by inflammation.
ostiomeatal complex is patent, could reduce the need for
computed tomography scans. The link between nitric oxide Nitric oxide is secreted in the respiratory tract with a
production and ciliary beating requires further exploration. major contribution from the upper airways especially the
Therapeutic adjustments to nitric oxide production are paranasal sinuses [1,2]. The biological significance of
under investigation. the airway-derived nitric oxide is still uncertain. Nitric
Summary oxide has been proposed as a bronchodilator [3], a vaso-
Nitric oxide is likely to prove highly relevant to airways dilator [4,5] and a major neurotransmitter [6,7], and to have
defence, as well as being an inflammatory mediator. Nasal antimicrobial [8,9], antitumour [10,11] and mucociliary
nitric oxide probably explains some of the benefit of nasal regulating activities [12–14] and also to act as an airborne
rather than mouth breathing. messenger [15,16]. It may also have pro-inflammatory
actions [17–19]. This review concentrates on recent
Keywords advances in knowledge about airways nitric oxide, its
allergic rhinitis, asthma, nitric oxide, primary ciliary measurement and significance for clinicians. It is predom-
dyskinesia, rhinosinusitis inantly concerned with the upper airways, but also deals
with fractional exhaled nitric oxide (FeNO) from the lower
Curr Opin Otolaryngol Head Neck Surg 15:258–263. ß 2007 Lippincott Williams & airways as well, since these measurements are likely to be
Wilkins.
of use to rhinologists seeking to confirm or exclude asthma
Royal National TNE Hospital, London, UK
in their patients.
Correspondence to Glenis Scadding, MA, MD, FRCP, Royal National TNE Hospital,
330 Grays Inn Road, London WC1X8DA, UK Exhaled nitric oxide from lower airway
E-mail: g.scadding@ucl.ac.uk Exhaled nitric oxide measurement provides a simple
Current Opinion in Otolaryngology & Head and Neck Surgery 2007, noninvasive means of measuring airway inflammation
15:258–263 in asthma, even in children [20]. Levels of FeNO corre-
Abbreviations late with eosinophilic airway inflammation and raised
FeNO fractional exhaled nitric oxide levels predict steroid responsiveness [21–23]. FeNO
FnNO nasal nitric oxide measurements are as accurate as sputum eosinophilia
iNOS inducible nitric oxide synthase
PCD primary ciliary dyskinesia in asthma diagnosis, with a sensitivity of 88% and speci-
ppb parts per billion ficity of 79%, but are simpler and quicker to perform [24].
With the use of FeNO measurements, maintenance
ß 2007 Lippincott Williams & Wilkins doses of inhaled corticosteroids can be reduced without
1068-9508
compromising asthma control [25]. Conversely, elevated
exhaled nitric oxide levels are associated with daily lung
function declines and increased medication usage in
urban children with moderate to severe asthma, despite
use of inhaled corticosteroids and long-acting beta
agonists [26], and predict relapse in children after
discontinuation of steroids, with an FeNO of 49 parts
per billion (ppb) at 4 weeks postdiscontinuation having a

258

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 Nitric oxide in the airways Scadding 259

Table 1 Uses of exhaled nitric oxide measurements Nasal nitric oxide has been reported as decreased in acute
eNO diagnostic use eNO other uses rhinosinusitis [30], nasal polyposis [31], primary ciliary
dyskinesia [32] and cystic fibrosis [33,34], and as normal

>20 ppb-asthma likely
Level relates to asthma severity

<8 ppb-asthma unlikely
Mild <30 >moderate or increased in allergic rhinitis [35–37]. In chronic rhi-
< severe >90 nosinusitis, Lindberg et al. [38] found lower nasal nitric

Intermediate values—perform
level also relates to adherence oxide levels than in healthy controls; Arnal et al. [39]
a methacholine challenge
and control

raised eNO predicts an found no significant difference.
FEV1 response to corticosteroid
eNO, exhaled nitric oxide; FEV1, forced expiratory rate in 1s.
Measurement of nasal nitric oxide
It is possible to measure gaseous nitric oxide by
sensitivity of 71% and a specificity of 93% for asthma chemiluminescence. Guidelines for FeNO and FnNO
relapse [27]. A large population study of 2200 adults has measurement have recently been produced [40].
shown that height, but not gender; asthma symptoms in
past month, reported use of inhaled steroids and atopy Stark et al. [41] suggested that the measurement should
were positively and independently associated with be made at the same time of day. Struben et al. [42
]
FeNO, while there was a negative association with found no significant diurnal variation when examining
smoking. The median value was 16 ppb with a range the effect of aspiration flow on nasal nitric oxide concen-
from 2.4 to 199 ppb [28
]. The uses of FeNO are sum- trations in air samples from one nostril, comparing FnNO
marized in Table 1. values and time to plateau in both nostrils with three
aspirations and assessing a short-term and long-term
Nasal nitric oxide from upper airway reproducibility. Mean FnNO at flows of 280 700 and
The situation in the upper respiratory tract is more 1200 ml per minute differed significantly (P < 0.01) at
complex. As in the lower airway, epithelial cells lining 854, 474, and 380 ppb. The plateau was reached more
the tract contain inducible nitric oxide synthase (iNOS) slowly with the slower flow levels. The within-subject
and will form nitric oxide in response to inflammatory variability was always less than 5%. There was no differ-
stimuli (Fig. 1). In the sinuses, however, nitric oxide is ence in FnNO between left and right nostrils. FnNO
continually formed at levels around 20–25 parts per values after 6 h, 24 h and 7 days were not significantly
million (ppm), which are toxic to bacteria, viruses, fungi different. The measurement was reproducible, feasible,
and tumour cells and may form part of the upper airway and best with an aspiration flow of 700 ml/min.
defence. Theoretically, nasal nitric oxide (FnNO) levels
have been postulated to depend mainly on the amount of The production of nitric oxide by different sinuses and
nitric oxide produced by the ciliated epithelium of the the effect of intravenous arginine have been investigated
paranasal sinuses and the size of the paranasal sinus ostia in a volunteer [43]. Nitric oxide output in the nose was
[29]. largely unaffected by gaseous carbon dioxide; however,
production in the frontal and maxillary sinuses was pro-
Figure 1 The very different levels of nitric oxide in sinuses,
upper and lower airways
foundly inhibited by it. In both sinuses, suppression by
carbon dioxide was countered by oxygen. Alterations in
oxygen or carbon dioxide in the maxillary antrum did not
NO in respiratory tract alter nitric oxide output in the frontal sinus or vice versa.
After arginine, nasal nitric oxide output remained elev-
Continuous production ated for more than 1 h.
in sinuses
Inducible in airways
Humming has been shown to increase the passage of
nitric oxide from the sinuses into the nose [44]. The
phenomenon has been investigated using a syringe
model [45]. Computer modelling of this suggests that
alternating pressure in the nasal cavity forces the air plug
20–25 ppm
in the sinus resonators to vibrate, thus expelling from the
400–900 ppb cavity nitric oxide gas, which is trailed in the exhalatory
airstream. Humming has been suggested as a test of
<20 ppb patency of the ostiomeatal complex [44]; it improves
discrimination between healthy controls and children
with cystic fibrosis better than static nitric oxide measure-
Values given are the ranges from our laboratory using a Logan Sinclair
NO Analyser.
ments [46

]. Sounding airflow during aerosol inhalation
increases drug deposition in sinuses [47
]. Therapeutic

Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 260 Allergy
effectiveness of continued humming in chronic rhino-
sinusitis has been suggested in a single case report [48].
Nasal nitric oxide is reduced in sleep and may be
involved in sleep physiology [49
].
Diagnostic uses of nasal nitric oxide
The value of nasal nitric oxide measurements is not yet
clearly defined but very low levels (90% lower than in
normal subjects) are consistently found in primary ciliary
dyskinesia (PCD) in which condition the epithelial cells
lack iNOS (Fig. 2). In a recent study [50], nasal nitric
oxide was significantly lower in those children with
proven PCD (geometric mean; 13.7 ppb), compared with
those who had negative biopsy results (132.7 ppb) and
healthy control subjects (223.7 ppb). The measurement
of nasal nitric oxide in this study population showed,
below a cut-off level of less than 105 ppb, a specificity of
88% for PCD, and positive predictive value of 89%. Nasal
nitric oxide above a cut-off level of 105 ppb excluded
PCD with a 100% certainty. The lower levels of exhaled
Figure 2 Possible implications of abnormal nasal nitric oxide
levels
Raised levels indicate an inflammatory nasal process and suggest
ostiomeatal complex patency. If inflammation causes sufficient swelling
and mucus so that sinus orifices are obscured [nasal polyposis, chronic
rhinosinusitis,cysticfibrosis(CF)],however,thennasalnitricoxidelevelsare
reduced. Levels within that found in the normal population do not therefore
necessarily imply normality. Very low levels are found in primary ciliary
dyskinesia. Nasal nitric oxide greater than 105 ppb excludes this diagnosis
with 100% certainty [50]. It is our practice to attempt decongestion (short
termwith alphaagonist,orbrief use oforalandtopicalcorticosteroids) when
ultralow levels are found followed by repeated nitric oxide measurement.
This reduces the number of referrals needed for ciliary studies. Figs 1 and 2
are from Scadding GK and Lund VJ, Investigative Rhinology, 2004, used
with permission of the publisher Taylor & Francis, London.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
nitric oxide in patients with PCD did not reach statistical
significance [50]. Exhaled breath condensate [51
] has
also been used as a means of nitric oxide measurement.
This may aid diagnosis of PCD in neonates [52
].
FnNO and FeNO measurements may be useful in the
coughing child in whom asthma is suspected but not
proven. In the presence of a normal FeNO and abnormal
FnNO, my suggestion is that the upper respiratory tract
should be targeted for therapy and the lower respiratory
tract monitored.
Allergic rhinitis
Several studies have attempted to assess nasal nitric oxide
levels in allergic rhinitis, with differences in results.
Further investigation by studying airway nitric oxide in
18 patients with birch pollen allergic rhinitis during
seasonal exposure and 18 controls [53] showed that
allergic rhinitis subjects were characterized by no differ-
ence in nasal nitric oxide, but higher orally exhaled nitric
oxide and a larger interindividual spread in nasal and
orally exhaled nitric oxide compared with controls. There
was a greater reduction in nasal nitric oxide after
L-NAME (an iNOS inhibitor) in patients compared with
controls. Nitric oxide production in the nasal mucosa of
patients with allergic rhinitis may be upregulated. On the
other hand, this increase could be counteracted by swel-
ling of the mucosa and secretions resulting in impaired
nitric oxide diffusion from, for example, the paranasal
sinuses, where particularly high levels of nitric oxide
have been found. Also, the high background levels of
nitric oxide from constitutive sources in the nose may
blunt smaller increases in mucosal nitric oxide output.
Methods for measurement of nasal nitric oxide need to be
improved and standardized before this test can be used in
monitoring inflammation in allergic rhinitis.
When compared with healthy subjects, patients with
allergic rhinitis exhibit an increased concentration of
exhaled adenosine and a related increase in exhaled nitric
oxide concentration. Exhaled breath condensate adeno-
sine is further increased when rhinitis patients inhale
through their nose rather than via their mouth. This
suggests that nonasthmatic patients with rhinitis may
have subclinical inflammation in their lower airways
[54]. In nasal allergen challenge, the level of nasal nitric
oxide falls more than that of exhaled nitric oxide in the
early-phase response, but in the late-phase response the
expired nitric oxide level falls whereas the nasal nitric
oxide level stays relatively constant [55]. Exposure to
Aspergillus increases FeNO, but not FnNO, in normal and
allergic subjects [56].
Chronic rhinosinusitis
Other uses have recently been suggested for nasal nitric
oxide measurements. Ragab et al. [57] found that nitric

oxide correlated well with computed tomography
changes, and the percentage rise in nasal nitric
oxide seen on medical and surgical treatment of chronic
rhinosinusitis correlated with changes in symptom
scores, saccharine clearance time, endoscopic changes
(all P < 0.001), polyp grades (P < 0.05 at 6 months,
P < 0.01 at 12 months) and surgical scores (P < 0.01).
There was no significant correlation with age, sex, smok-
ing or allergy. The authors suggested that nasal nitric
oxide provides a valuable noninvasive objective measure
of the response of chronic rhinosinusitis to therapy,
but that topical nasal corticosteroids may be needed
to reduce the contribution of nasal epithelial nitric
oxide and allow that emanating from the sinuses to be
measured.
Treatment effects
FnNO can be used to examine treatment effects. It has
been shown that topical nasal corticosteroids reduce
elevated FnNO in allergic rhinitis, but raise FnNO levels
in nasal polyposis [31]. The combination of topical
steroids to nose and chest was significantly better than
montelukast and cetirizine in reducing FnNO and FeNO
[58
]. Saline has been shown to cause vasoconstriction
and reduce nitric oxide in the nose [59].
Nitric oxide adjustment is also being tried therapeuti-
cally. S-nitrosoglutathione which, like nitric oxide, is low
in the cystic fibrosis airway, has been used in vitro on
epithelia from patients with cystic fibrosis for patients
where it appears to have increased chloride flux [60]. The
correlation between endogenous nitric oxide and ciliary
beating was explored by Alberty et al. [61
] in an in-vitro
model using cultures of nasal mucosa. Blocking of
the endogenous nitric oxide synthesis in TNF-alpha/
LPS-stimulated cultures reduced baseline ciliary beat
frequency (CBF) by 10.6þ/2.1% (P < 0.05) but the
effect of mechanical ciliostimulation on CBF remained
unchanged. They concluded that endogenous NO-depen-
dent and Ca(2þ)-dependent mechanical stimulation of
ciliary activity probably use independent intracellular
signalling pathways.
The pathophysiological effects of nitric oxide are not yet
fully understood. There appears to be an intimate link
between nitric oxide production and the ability of cilia to
beat, demonstrated above, in PCD and in the Ragab
study. Recently [62
], a decrease in maximal nitric oxide
output from conducting airways was associated with
limited airflow impairment in PCD. The recent discovery
of a novel mechanism of nitric oxide modulation of
apoptosis, in which human airway epithelial cells exposed
to nitric oxide via a nitric oxide donor induce ceramide
generation via ceramide synthase. This ceramide induc-
tion does not lead to apoptosis, however, unless acidic
sphingomyelinase(aSMase) is knocked down, allowing
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nitric oxide in the airways Scadding 261
the release of caspase-3, its activation and execution
of apoptosis [63].
Inhibitors of iNOS are under development as treatment
for inflammatory airways disorders. It is to be hoped that
iNOS inhibition is not detrimental to the defence of
the airways.
Conclusion
Nitric oxide is a highly conserved molecule that is
of importance in many processes in the airways,
both protective and inflammatory. Much remains to
be elucidated about its functions and interactions. At
present, measurements of FeNO are of use in asthma
diagnosis and therapy, and nasal nitric oxide monitoring
is helpful in the diagnosis of primary ciliary dyskinesia,
but may also prove valuable in chronic rhinosinusitis,
both in assessment of ostiomeatal patency and in asses-
sing outcomes. Therapeutic use of iNOS inhibitors
and nitric oxide donors is likely to increase under-
standing of the pathophysiology of nitric oxide and its
metabolites.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:

of special interest


of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (p. 291).
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Nitric oxide in the airways Scadding 263
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