respiratory investigation ] (] ] ] ]) ] ] ] ] ] ]

Contents lists available at ScienceDirect

Respiratory Investigation
journal homepage: www.elsevier.com/locate/resinv

Original article

Airway remodeling associated with cough

hypersensitivity as a consequence of persistent
cough: An experimental study
Hitoshi Nakajia, Akio Niimi, MD, PhDa,b,n, Hirofumi Matsuokaa,
Toshiyuki Iwataa, Shilei Cuia, Hisako Matsumotoa, Isao Itoa, Tsuyoshi Ogumaa,
Kojiro Otsukaa, Tomoshi Takedaa, Hideki Inouea, Tomoko Tajiria,
Tadao Nagasakia, Yoshihiro Kanemitsua,b, Kazuo Chinc, Michiaki Mishimaa
a

Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate School of
Medical Sciences, 1 Kawasumi, Mizuho-Cho, Muzuho-Ku, Nagoya 467-8601, Japan
c
Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
b

art i cle i nfo

ab st rac t

Article history:

Background: Chronic cough involves airway remodeling associated with cough reex

Received 16 September 2015

hypersensitivity. Whether cough itself induces these features remains unknown.

Received in revised form

Methods: Guinea pigs were assigned to receive treatment with citric acid (CA), saline (SA), or

31 May 2016

CAdextromethorphan (DEX). All animals were exposed to 0.5 M CA on days 1 and 22. On days

Accepted 27 June 2016

420, the CA and CADEX groups were exposed to CA, and the SA group to saline thrice
weekly, during which the CADEX group was administered DEX pretreatment to inhibit cough.

Keywords:
Chronic cough
Airway remodeling
Cough reex hypersensitivity
Airway smooth muscle
Mechanical stress

The number of coughs was counted during each 10-min CA or SA exposure. Terbutaline
premedication was started to prevent bronchoconstriction. Bronchoalveolar lavage and
pathology were examined on day 25. Average cough number for 10 CA exposures was
examined as cough index in the CA group, which was divided into frequent (cough index45)
and infrequent (o5) cough subgroups for lavage and pathology analysis.
Results: The number of coughs signicantly increased in the CA group from day 13 onwards. In
the CADEX and SA groups, the number of coughs did not differ between days 1 and 22, while
average number of coughs during days 420 was signicantly lower than at days 1 and 22.
Bronchoalveolar cell proles were similar among the four groups. The smooth muscle area of
small airways was signicantly greater in the frequent-cough subgroup than in the other
groups (in which it was similar), and highly correlated with cough index in CA group.
Conclusion: Repeated cough induces airway smooth muscle remodeling associated with cough
reex hypersensitivity.
& 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

n
Corresponding author at: Department of Respiratory Medicine, Allergy and Clinical Immunology, Nagoya City University Graduate
School of Medical Sciences, 1 Kawasumi, Mizuho-Cho, Muzuho-Ku, Nagoya 467-8601, Japan. Tel.: 81 52 853 8214; fax: 81 52 852 0849.

http://dx.doi.org/10.1016/j.resinv.2016.06.005
2212-5345/& 2016 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Nakaji H, et al. Airway remodeling associated with cough hypersensitivity as a consequence of
persistent cough: An experimental study. Respiratory Investigation (2016), http://dx.doi.org/10.1016/j.resinv.2016.06.005

respiratory investigation ] (] ] ] ]) ] ] ] ] ] ]

1.

Introduction

Chronic cough is an important clinical problem. Asthmarelated diagnoses such as cough-variant asthma involve
eosinophilic airway inammation [1,2]. Cough may also be
ascribed to non-asthma-related diagnoses, such as gastroesophageal reux disease, but in some patients, it remains
unexplained despite thorough investigations. Such nonasthmatic chronic cough (NACC) also involves airway inammation characterized by increased neutrophils, mast cells, or
lymphocytes [24].
Airway remodeling is another feature of asthma [5]. The
pathological changes of remodeling in cough-variant asthma
include subepithelial thickening, goblet-cell hyperplasia, vascular proliferation, and airway-wall thickening [2,6,7]. Eosinophilic bronchitis also involves similar changes [8]. These
changes may be ascribed to eosinophil-derived brogenic
mediators such as transforming growth factor (TGF)-beta,
and may result in accelerated lung function decline in
intractable cases [1], as in asthma [5]. Interestingly, cases of
NACC without airway eosinophilia also show features of
remodeling, such as subepithelial thickening, increase of
airway smooth muscle (ASM), goblet cells and vessels,
epithelial shedding, airway-wall thickening [2,3,7], and irreversible airow obstruction [9]. Especially noteworthy is the
increase of ASM despite absence of airway hyperresponsiveness [10].
The pathogenesis and functional consequences of airway
remodeling are not precisely known in chronic cough, especially for NACC [10]. Airway epithelium exposed to compressive stresses, an effect mimicking acute bronchoconstriction
in asthma, increases its expression of genes relevant to
remodeling, such as TGF-beta 2. Synthesis of extracellular
matrix by cocultured broblasts is also increased [11]. Cough
may also exert mechanical stress on the airway mucosa [12].
In patients with NACC, TGF-beta 1 levels and neutrophil
counts in bronchoalveolar lavage uid (BALF), as well as
subepithelial thickness, were increased [13]. TGF-beta
1 expression in the epithelium and ASM were also increased,
and TGF-beta 1 levels correlated with subepithelial thickness
[13]. In NACC patients, the degree of remodeling (as indicated
by goblet-cell hyperplasia, epithelial shedding, and airwaywall thickening) correlated with cough reex sensitivity to
capsaicin [2,7]. Persistent cough may thus result in airway
remodeling, in the presence or absence of inammation. This
may lead to cough reex hypersensitivity that might induce
further cough, creating a vicious cycle [10].
A guinea pig model of airway collapse mimicking cough
has been reported, induced by rapid repetition of negative
pressure applied to the airways of articially ventilated
animals [14]. Capsaicin sensitivity and BALF neutrophils
Abbreviations: CA,

citric acid; ASM,

airway smooth muscle; BAL,

transiently increased 6 hours after stimulus, and these

features correlated with each other. However, this was a
short-term experiment, failing to examine remodeling
changes [14].
We investigated whether repeated induction of cough in
awake guinea pigs is associated with airway remodeling and
cough reex hypersensitivity. Cough was induced by citric
acid (CA) exposure, which is unlikely to induce tachyphylaxis
and therefore useful for repeated cough induction and measurements [1517].

2.

Materials and methods

2.1.

Animals

Male Dunkin-Hartley guinea pigs were obtained and quarantined. All animal procedures conformed to Kyoto University's regulations on animal experimentation (Med Kyo 04449;
approval date: Nov 25, 2004).

2.2.

Experimental design

Nave guinea pigs were assigned to one of three treatment

groups: CA group, saline (SA) group, or CAdextromethorphan
(DEX) group (Fig. 1). On days 1 and 22, guinea pigs in all groups
were exposed to CA (0.5 M via nebulizer for 10 min) and the
number of coughs was counted. From days 4 through 20, the CA
and CADEX groups were exposed to 0.5 M CA, and the SA group
to 0.9% saline for 10 min, three times weekly, at 2- or 3-day
intervals (eight times in total). During this period, the CADEX
group was treated with 30 mg/kg DEX intra-peritoneally (i.p.)
30 min prior to CA exposure, to inhibit cough. DEX was not
administered on days 1 and 22. In the CA group, the mean
number of coughs for 10 CA exposures was calculated as the
cough index for each animal. The CA group was divided into a
frequent cough subgroup (CA-F: Cough index Z5) and an
infrequent cough subgroup (CA-I: Cough index o5) for analysis
of BAL and pathology results. The median number of cough
index ( 5) of the 18 animals in the CA group was used as the cut
off level.

2.3.

System for cough measurement

Guinea pigs were placed in a chamber allowing free movement and equipped with an internal microphone and a
pressure transducer [18]. They were connected to an Amplier Interface Unit series pre-amplier (EMMS, Bordon, UK).
The chamber was provided airow by a Basic Flow Supplier
AIR 200 (EMMS) at 1500 mL/min. The changes in airow
induced by respiration and cough were recorded by a pneumotachograph. Cough sounds were amplied and recorded
bronchoalveolar lavage; BALF,

BAL uid; PAS,

periodic acid-

Schiff; TGF, transforming growth factor; NACC, non-asthmatic chronic cough

E-mail addresses: nakaji@ace.ocn.ne.jp (H. Nakaji), a.niimi@med.nagoya-cu.ac.jp (A. Niimi),
h-matsuoka@shinkohp.or.jp (H. Matsuoka), tsyk.iwata@gmail.com (T. Iwata), cuishilei79@gmail.com (S. Cui),
hmatusmo@kuhp.kyoto-u.ac.jp (H. Matsumoto), isaoito@kuhp.kyoto-u.ac.jp (I. Ito), toguma@kuhp.kyoto-u.ac.jp (T. Oguma),
kotsuka@kcho.jp (K. Otsuka), takeda@jinsen.jp (T. Takeda), inouehid@kuhp.kyoto-u.ac.jp (H. Inoue),
tomokot@kuhp.kyoto-u.ac.jp (T. Tajiri), nagasaki@kuhp.kyoto-u.ac.jp (T. Nagasaki), kaney32@med.nagoya-cu.ac.jp (Y. Kanemitsu),
chink@kuhp.kyoto-u.ac.jp (K. Chin), mishima@kuhp.kyoto-u.ac.jp (M. Mishima).

Please cite this article as: Nakaji H, et al. Airway remodeling associated with cough hypersensitivity as a consequence of
persistent cough: An experimental study. Respiratory Investigation (2016), http://dx.doi.org/10.1016/j.resinv.2016.06.005

respiratory investigation ] (] ] ] ]) ] ] ] ] ] ]

magnication of  400 in one section and examined. Each

image was separated by 4200 mm. ASM area and submucosal
area were measured with hematoxylin and eosin (H&E)
staining. Epithelial area, goblet cell area, and length of basement membrane were measured using periodic acid-Schiff
(PAS)-stained slices. Areas of goblet cells were measured as
the total of PAS-positive areas. Each index was calculated
(Fig. 2a) from an average of three images for each animal.
Fig. 1 Experimental protocol. Guinea pigs in all groups
were exposed to CA (0.5 M) on days 1 and 22 for the
evaluation of cough sensitivity. On days 4 through 20, the
CA group (n 18) and CADEX group (n 9) were exposed to
CA, and the SA group (n 9) to saline three times per week.
During this period, the CADEX group was treated with
30 mg/kg DEX i.p. 30 min prior to CA exposure to inhibit
cough. Terbutaline (0.05 mg/kg) was administered i.p. prior
to each CA or SA exposure in all groups. CA: Citric acid, SA:
Saline, DEX: Dextromethorphan.

by microphone. Guinea pig behavior was captured with an

external camera. Data acquisition was performed with eDacq
software (EMMS) [18].
After dosing with 0.05 mg/kg terbutaline i.p. to prevent
bronchoconstriction [16,18], 0.5 M CA or 0.9% saline was
delivered using a nebulizer with an output of 0.5 mL/min
for 10 min (Fig. 1). The number of coughs over each 10-min
exposure was counted, distinguished from sneezing by guinea pig posture, pressure changes, and sound.

2.4.

BAL

R specimens were cannulated with a catheter connected to a

syringe, and washed thrice with 4 mL saline. After centrifugation of the collected BALF, total cells were counted and
differentials (macrophages, neutrophils, eosinophils, lymphocytes, and epithelial cells) were analyzed.

2.6.

Histological measurements

Digitally photographed sections were analyzed using a quantication software (ImageJ, U.S. NIH, Bethesda, MD, USA). The
large and small airways were examined.

2.6.1.

Small airways

In sections of L specimens, airways with internal diameters

o1000 m were examined. Two or three airways at a magnication of  200 were photographed, and the pathological
changes were assessed (Fig. 2b). Goblet cells were unavailable
because PAS staining was negative.

2.7.

Statistical analysis

Data are expressed as mean7SE. p valueso0.05 were considered statistically signicant. Multiple groups were compared by one-way ANOVA, followed by Fisher's PLSD test. The
number of coughs on days 122 among the three groups was
analyzed by the KruskalWallis test. Correlations were analyzed using Pearson's correlation coefcient. The difference
in the number of coughs between days 1 and 22, and the
difference in the mean number of coughs on days 1 and 22
from that on days 420 between the CADEX group and the
SA group were analyzed using a paired t-test. Changes in
cough numbers in the CA group were analyzed with repeated
measures ANOVA.

Sacrice and tissue processing

On day 25, all guinea pigs were anesthetized with sodium

pentobarbital i.p. The trachea and lungs were removed
together and ligated at the origin of the left main bronchus.
The sample was divided into proximal trachea (T), distal
trachea with right lung (R), and left lung (L), by cutting the
trachea at 1 cm proximal from the bifurcation and left main
bronchus just distal to the ligature. After xation with 4%
paraformaldehyde, 3-m-thick sections were cut at the distal
end of T and at 1 cm distal from the original cut end of L.

2.5.

2.6.2.

Large airways

Sections from T specimens were examined. For each animal,

three images (200 m square) were photographed at a

3.

Results

3.1.

Change in number of coughs

The number of coughs in the CA group increased during the

experimental period (po0.05). This was rst recognized on
day 13, and was seen consistently and signicantly thereafter
until day 22 (Fig. 3a). In the CADEX and SA groups, the
number of coughs did not differ between days 1 and 22, while
the mean number of coughs on days 420 was lower than
that on days 1 and 22 (p 0.025 and 0.011, respectively;
Fig. 3bc). Saline induced no coughs.
The number of coughs differed signicantly on days 420
except for day 8 among the three groups, while those on day
1 and on day 22 did not differ (Fig. 3, bottom). The mean
number of coughs on days 420 differed among the three
groups (7.871.7 for the CA group, 2.470.7 for the CADEX
group, and 070 for the SA group, p 0.0067), and was higher
in the CA group than in the CADEX group (p 0.046) and the
SA group (p 0.0035). The difference between the latter two
groups was also signicant (p 0.0003).

3.2.

Inammatory cells in BALF

The CA group was divided into two subgroups as above. The four
groups (CA-F, CA-I, SA, and CADEX) did not differ in terms of
neutrophil or eosinophil percentage or count (Figs. 45). The
numbers of both cell types were unrelated to cough index in the

Please cite this article as: Nakaji H, et al. Airway remodeling associated with cough hypersensitivity as a consequence of
persistent cough: An experimental study. Respiratory Investigation (2016), http://dx.doi.org/10.1016/j.resinv.2016.06.005

respiratory investigation ] (] ] ] ]) ] ] ] ] ] ]

Goblet cells

Epithelium

Goblet cells

Basement
membrane
ASM

Submucosa

50 m

Cartilage

Adventitia
Smooth muscle

Basement
membrane
Epithelium
100 m
Fig. 2 Images of large and small airways and their schema. (a) Large airway (trachea) airway smooth muscle (ASM) index (%):
[ASM area/submucosal area]  100 Epithelial thickness (m): epithelial area (including goblet cells)/length of basement
membrane Goblet cell index (%): [PAS-positive area/epithelial area]  100. (b) Small airway ASM index (%): [ASM area/total wall
area]  100 Epithelial thickness (m): Epithelial area/length of basement membrane.
CA group, or to the mean number of coughs on days 1 and 22 in
the CADEX or SA group (data not shown).
Total cell count, and percentage or count of macrophages,
lymphocytes, and epithelial cells did not differ among the
four groups (data not shown).

3.3.

Histology

3.3.1.

Large airways

Neither ASM index, epithelial thickness, or goblet cell index

differed among the four groups (Fig. 6). Cough index was
unrelated to any pathological parameters in the two CA
subgroups combined (data not shown).

3.3.2.

Small airways

ASM index was higher in the CA-F subgroup than in the other
groups, in which it was similar (Fig. 7a). Cough index
correlated highly with ASM index in the two CA subgroups
combined (Fig. 7b), but not in the other groups (data not
shown). Epithelial thickness was similar among the groups
(Fig. 7c) and was unrelated to cough index in the two CA
subgroups combined (data not shown). Fig. 8 shows representative images.

4.

Discussion

We demonstrated that repeated cough induced by CA exposure was associated with heightened cough reex sensitivity
and airway remodeling (increased ASM) in small airways,
without evidence of cellular inammation, in guinea pigs.

Previous animal studies of cough mostly investigated the

effects of allergen challenge or drug intervention on cough
sensitivity. To our knowledge, this is the rst study of the
effect of repeated cough on cough reex sensitivity and
airway pathology.
In asthma, airway remodeling has been ascribed to eosinophilic inammation, but noninammatory mechanisms
have also been suggested [5]. An alteration of the relationships between the epithelium and myobroblasts could lead
to structural changes, as could mechanical stimuli. Bronchoconstriction produces folding of the airway wall, inducing
stress on the epithelium and leading it to produce brogenic
factors [11]. Bronchoconstriction without additional inammation, elicited by inhaled methacholine, induces airway
remodeling changes in asthmatics [19]. Likewise, the repetitive mechanical and physical effects of coughing on the
airways may also result in airway remodeling. Cough consists
of deep inspiration followed by forced rapid expiration [12].
The airways are compressed and narrowed during such
expiration; the narrowing results from a transmural gradient
between the extraluminal and intraluminal pressures [12].
Immediately before the expiration phase, both extraluminal
and intraluminal pressures of the large airways become
positive. In the expiration phase, intraluminal pressure suddenly decreases to ambient pressure, resulting in a large
transmural pressure that compresses the airways [12,14].
Various remodeling changes observed in chronic cough
patients [2,7] indicate the pathogenetic role of such nonspecic effects of coughing on remodeling, but it is also interesting that remodeling changes correlated with cough reex
sensitivity [2,7].

Please cite this article as: Nakaji H, et al. Airway remodeling associated with cough hypersensitivity as a consequence of
persistent cough: An experimental study. Respiratory Investigation (2016), http://dx.doi.org/10.1016/j.resinv.2016.06.005

respiratory investigation ] (] ] ] ]) ] ] ] ] ] ]

Fig. 3 Changes in number of coughs during serial challenges in the three groups (a) CA group: the number of coughs
signicantly increased on day 13, and persisted until day 22. (b) CADEX group: there was no signicant difference in the
mean number of coughs between day 1 and day 22. (c) SA group: there was no signicant difference in the number of coughs
between day 1 and day 22. Data plots and bars are presented as the mean number of coughs7SE for each exposure. p values
for differences between the three groups by ANOVA are presented at the bottom of Fig. 3. *po 0.05 by repeated measures
ANOVA. NS: not signicant by paired t-test.

In this study, increased cough reex sensitivity after

repeated CA exposure was associated with an increase in
small airways ASM. Cough index correlated with ASM index.
These are consistent with our clinical observations [2,7] and a
biopsy study showing increased expression of TGF-beta 1 and
transcription factor Smad 2/3 in ASM of NACC patients [13].
Chronic cough thus may induce the production of growth
factors, leading to remodeling. An increase in ASM might also
have resulted in cough hypersensitivity. Increased expression
of capsaicin receptor TRPV-1 has been shown specically in
ASM of NACC patients [20]. ASM produces various mediators,
including prostaglandin E2 (PGE2)[21], which has a tussive
action and shows increased sputum levels in chronic cough
patients [22]. TGF-beta 1 stimulates PGE2 production from
ASM cells [23]. The series of changes observed in ASM of

NACC patients (increased volume [2] and expression of TGFbeta 1 [13] and TRPV-1 [20]) in conjunction with our results
may imply novel mechanisms of cough involving ASM. The
reason why ASM changes were conned to small airways in
our study is uncertain, but in asthma, spirometry indices of
small airway obstruction emerge earlier in the disease [24].
Mechanical and physical effects of coughing may have a
greater effect on small airways, which lack cartilage and have
thinner walls and smaller lumens, and are therefore more
likely to collapse.
Cellular inammation was absent in our model. Hara and
colleagues induced neutrophilic inammation and cough
reex hypersensitivity by repeated pressure stress on airways, supporting an assumption that the trauma of coughing
may induce non-specic inammation [14]. However, BAL

Please cite this article as: Nakaji H, et al. Airway remodeling associated with cough hypersensitivity as a consequence of
persistent cough: An experimental study. Respiratory Investigation (2016), http://dx.doi.org/10.1016/j.resinv.2016.06.005

respiratory investigation ] (] ] ] ]) ] ] ] ] ] ]

Fig. 4 Inammatory cells in BALF in the four groups (a: neutrophils, b: eosinophils). There was no difference in the number of
neutrophils or eosinophils among the groups. SA: saline group (n 8), CA: citric acid group; CA-I: infrequent cough subgroup
(n 9), CA-F: frequent cough subgroup (n 9), CADEX: CAdextromethorphan group (n 7).

Fig. 5 Inammatory cells in BALF (a: neutrophils, b: eosinophils). The four groups did not differ in terms of neutrophil or
eosinophil count. SA: saline group, CA: citric acid group; CA-I: infrequent cough subgroup, CA-F: frequent cough subgroup,
CADEX: CAdextromethorphan group.

neutrophilia disappeared 12 h after the pressure stress. We

examined BAL 72 h after the nal CA challenge, aiming to
detect chronic rather than acute inammation, which is more
relevant to airway remodeling.
We exposed animals to CA to induce cough and investigate
the effect of repeated prolonged cough. Other methods of cough
induction or mimicking (mechanical stimuli [25] or pressure
changes [14]) were unsuitable, since they require anesthesia,
surgical procedures, and mechanical ventilation, and thus cannot be repeated chronically. One might assume that repeated CA
challenges could result in tachyphylaxis and decreased cough
response, but this was unlikely to happen, because repeated
challenges with 0.5 M CA at an interval of at least 2 days do not
elicit tachyphylaxis [16]. Recently, guinea pigs repeatedly
exposed to CA every 4 days until day 12 showed no change in
the number of coughs induced [17]. These results were in broad
agreement with ours, in which cough reex hypersensitivity was
rst recognized on day 13 and persisted until day 22. Cough
reex sensitivity may thus increase when cough is induced for a
longer period.

Other issues associated with the use of CA are its bronchoactive properties, and possible direct effects on airway inammation/pathology. In our study, guinea pigs were treated with
0.05 mg/kg terbutaline prior to CA exposure, which effectively
inhibits bronchoconstriction without affecting cough [16]. In the
CADEX group, pathological changes were similar to those in
the SA and CA-I groups, and cough reex sensitivity was
unchanged. Given that DEX is a centrally acting antitussive
with no recognized anti-inammatory effect, potential effects
of CA on airways must have remained in the CADEX group,
while cough was signicantly suppressed. The increased cough
reex sensitivity and ASM induced in the CA group should
therefore be ascribed to repeated coughs rather than other
effects of CA.

5.

Conclusion

Repeated cough itself may induce airway remodeling associated with cough reex hypersensitivity. Cough may lead to

Please cite this article as: Nakaji H, et al. Airway remodeling associated with cough hypersensitivity as a consequence of
persistent cough: An experimental study. Respiratory Investigation (2016), http://dx.doi.org/10.1016/j.resinv.2016.06.005

respiratory investigation ] (] ] ] ]) ] ] ] ] ] ]

Fig. 6 Histological indices in the trachea (a: ASM index, b: epithelial thickness, c: goblet cell index). There were no differences
in any of the pathological indices among the groups. ASM: airway smooth muscle. See Fig. 4 for other abbreviations.

Fig. 7 Indices of airway remodeling in small airways (a) ASM index (%): ASM index was higher in the CA-F subgroup than in
the other groups. (b) Relationship between ASM index and cough index in the CA group: Cough index highly correlated with
ASM index in the two CA subgroups combined. (c) Epithelial thickness (lm): Epithelial thickness was similar among the
groups. *p: statistically signicant by Fisher's PLSD post-hoc test. See Figs. 4 and 6 for abbreviations.

Please cite this article as: Nakaji H, et al. Airway remodeling associated with cough hypersensitivity as a consequence of
persistent cough: An experimental study. Respiratory Investigation (2016), http://dx.doi.org/10.1016/j.resinv.2016.06.005

respiratory investigation ] (] ] ] ]) ] ] ] ] ] ]

Fig. 8 Representative photomicrographs of small airways of animals. The photomicrographs from the (a) SA group, (b) CA-I
subgroup, and (c) CA-F subgroup are shown. A marked increase in ASM is noted in the CA-F subgroup (arrows).
airway remodeling, and remodeling may be a cause of cough
reex hypersensitivity or chronic cough. The concomitance of
both mechanisms may lead to a positive feedback mechanism for cough persistence, possibly involved in chronic
intractable cough [10]. Another consequence of persistent
coughing and resultant airway remodeling may be irreversible airow obstruction, as suggested by a study of patients
with intractable nonasthmatic chronic cough [9]. Despite the
often-difcult treatment of chronic cough, clinicians should
make every effort to resolve coughing, not only for the sake of
patients quality of life, but also to avoid these undesirable
clinical and functional consequences.

Conict of interest
Akio Niimi received lecture fees from AstraZeneca, Astellas
and Kyorin, and received research funding from AstraZeneca
and Astellas. Isao Ito received a research grant. Tsuyoshi
Oguma received research funding from Olympus Corporation.
Kazuo Chin received lecture fees from Teijin HomeMedical
belongs to endowed departments sponsored by Teijin
Pharma, Philips & Respironics, Fukuda Denshi and Fukuda
Lifetec Keiji.

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Please cite this article as: Nakaji H, et al. Airway remodeling associated with cough hypersensitivity as a consequence of
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