title: Airway remodeling associated with cough hypersensitivity as a consequence of persistent cough: An experimental study.
abstract: BACKGROUND
  Chronic cough involves airway remodeling associated with cough reflex hypersensitivity. Whether cough itself induces these features remains unknown.
  
  
  METHODS
  Guinea pigs were assigned to receive treatment with citric acid (CA), saline (SA), or CA+dextromethorphan (DEX). All animals were exposed to 0.5M CA on days 1 and 22. On days 4-20, the CA and CA+DEX groups were exposed to CA, and the SA group to saline thrice weekly, during which the CA+DEX group was administered DEX pretreatment to inhibit cough. 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 index>5) and infrequent (<5) cough subgroups for lavage and pathology analysis.
  
  
  RESULTS
  The number of coughs significantly increased in the CA group from day 13 onwards. In the CA+DEX and SA groups, the number of coughs did not differ between days 1 and 22, while average number of coughs during days 4-20 was significantly lower than at days 1 and 22. Bronchoalveolar cell profiles were similar among the four groups. The smooth muscle area of small airways was significantly 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.
  
  
  CONCLUSIONS
  Repeated cough induces airway smooth muscle remodeling associated with cough reflex hypersensitivity.
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: nakaji@ace.ocn.ne.jp.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakaji
authors.affiliation: 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. Electronic address: a.niimi@med.nagoya-cu.ac.jp.
authors.forename: Akio
authors.initials: A
authors.lastname: Niimi
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: h-matsuoka@shinkohp.or.jp.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Matsuoka
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: tsyk.iwata@gmail.com.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Iwata
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: cuishilei79@gmail.com.
authors.forename: Shilei
authors.initials: S
authors.lastname: Cui
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: hmatusmo@kuhp.kyoto-u.ac.jp.
authors.forename: Hisako
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: isaoito@kuhp.kyoto-u.ac.jp.
authors.forename: Isao
authors.initials: I
authors.lastname: Ito
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: toguma@kuhp.kyoto-u.ac.jp.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Oguma
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: kotsuka@kcho.jp.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Otsuka
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: takeda@jinsen.jp.
authors.forename: Tomoshi
authors.initials: T
authors.lastname: Takeda
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: inouehid@kuhp.kyoto-u.ac.jp.
authors.forename: Hideki
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: tomokot@kuhp.kyoto-u.ac.jp.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tajiri
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: nagasaki@kuhp.kyoto-u.ac.jp.
authors.forename: Tadao
authors.initials: T
authors.lastname: Nagasaki
authors.affiliation: 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. Electronic address: kaney32@med.nagoya-cu.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kanemitsu
authors.affiliation: Department of Respiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: chink@kuhp.kyoto-u.ac.jp.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Chin
authors.affiliation: Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan. Electronic address: mishima@kuhp.kyoto-u.ac.jp.
authors.forename: Michiaki
authors.initials: M
authors.lastname: Mishima
mesh_terms: D056151:Airway Remodeling / Q000502:physiology*; D000818:Animals; D002908:Chronic Disease; D003371:Cough / Q000209:etiology*; D006168:Guinea Pigs; D008297:Male; D009130:Muscle, Smooth / Q000502:physiology; D012018:Reflex / Q000502:physiology*; D013314:Stress, Mechanical
keywords: Airway remodeling; Airway smooth muscle; Chronic cough; Cough reflex hypersensitivity; Mechanical stress