PACAP and airway regulation with special reference to smooth muscle and neutrophils

Johan Kinhult

Research output: ThesisDoctoral Thesis (compilation)

Abstract

The investigations focus on the neuropeptidepituitary adenylate cyclase-activating peptide and its effects on airway regulation, with emphasis on smooth muscle relaxation and neutrophil activation and migration. In the nasal mucosa, PACAP-containing nerve fibers were localized invascular smooth muscle and close to seromucous glands. In the lung, PACAP-containing nerve fibers were found close to seromucous glands and in smooth muscle layers of bronchi, as well as in the wall of pulmonary arteries. PACAP caused a concentration-dependent relaxation of precontracted human bronchial and pulmonary arterial segments. VIP (Vasoactive intestinal peptide), also present in the human lung, failed to relax the majority of the bronchial segments tested. In guinea pig, the carbon monoxide (CO) producing enzyme heme oxygenase (HO) was observed in airway smooth muscle bundles. PACAP-containing nerve fibers were localized in association with the same structures as HO. In addition, PACAP relaxed precontracted guinea pig tracheal segments via a CO-dependent mechanism, indicating a role for CO in PACAP-induced airway relaxation. Following activation, certain glycoproteins, like CD11b, CD66b and CD63, emanating from intracellular granules, can be expressed on the neutrophil cell surface. An increase in the expression of CD11b, CD66b and CD63 was found following the migration of neutrophils from the blood stream to the surface of the nasal mucosa, indicating the presence of activated neutrophils in the nose. During ongoing allergic rhinitis, the expression of CD11b on neutrophils derived from the nose was further increased suggesting augmented neutrophil activation. In contrast neutrophils from the blood exhibited a reduced expression of CD11b and CD66b. The latter might be a reflection of negative feedback mechanisms. Human neutrophils incubated with PACAP exhibited a marked increase in their surface expression of CD11b, CD66b and CD63. No such increases were found following incubation with VIP. In contrast, both peptides inhibited N-formylmethionyl-leucyl-phenylalanine (fMLP)-induced neutrophil chemotaxis. Application of PACAP in the human nose increased nasal airway resistance and augmented the increase in nasal resistance induced by histamine. In addition, PACAP inhibited histamine induced recruitment of neutrophils, increased plasma leakage and reduced the level of IL-1RA (an endogenously produced interleukin-1 receptor antagonist) in nasal lavage fluid. Altogether, the data presented in this thesis support the idea of PACAP as a modulator within the human airways, with a potential role in inflammatory diseases like allergy and asthma.
Original languageEnglish
QualificationDoctor
Awarding Institution
  • Laryngoesophagology, Allergy and Life Quality
Supervisors/Advisors
  • [unknown], [unknown], Supervisor, External person
Award date2003 Jan 17
Publisher
Print ISBNs91-628-5515-8
Publication statusPublished - 2003

Bibliographical note

Defence details

Date: 2003-01-17
Time: 13:00
Place: Lilla aulan, ingång 59 Medicinskt forskningscentrum, Universitetssjukhuset MAS, Malmö

External reviewer(s)

Name: Dahlqvist, Åke
Title: Doc
Affiliation: Institutionen för klinisk vetenskap, enheten för Öron-, Näs-, och Halssjukdomar, Umeå Universitet.

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Article: I Kinhult J, Andersson JA, Uddman R, Stjarne P, Cardell LO. (2000). Pituitary adenylate cyclase-activating peptide 38 a potent endogenously produced dilator of human airways. European Respiratory Journal, 15:243-7.II Kinhult J, Uddman R, Cardell LO. (2001). The induction of carbon monoxide-mediated airway relaxation by PACAP 38 in isolated guinea pig airways. Lung, 179:1-8.III Kinhult J, Egesten A, Benson M, Uddman R, Cardell LO. Increased expression of surface activation markers on neutrophils following migration into the nasal lumen during allergic rhinitis (submitted).IV Kinhult J, Egesten A, Uddman R, Cardell LO. (2002). PACAP enhances the expression of CD11b, CD66 and CD 63 in human neutrophils. Peptides, 23:1735-9.V Kinhult J, Uddman R, Laan M, Linden A, Cardell LO. (2001). Pituitary adenylate cyclase-activating peptide inhibits neutrophil chemotaxis. Peptides, 22:2151-4.VI Kinhult J, Adner M, Uddman R, Cardell LO. PACAP effects in the human nose (submitted).


The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Oto-Rhino-Laryngology (013243500), Reconstructive Surgery (013240300)

Subject classification (UKÄ)

  • Otorhinolaryngology

Keywords

  • audiology
  • auditive system and speech
  • Otorinolaryngologi
  • audiologi
  • hörsel- och talorganen
  • Otorhinolaryngology
  • allergy
  • neutrophils
  • smooth muscle
  • PACAP
  • airway regulation

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