Linköping University Medical Dissertations
No. 543

Regulation of Experimentally Induced Airway Obstruction

Eva G. Lindström

Akademisk avhandling som för avläggande av medicine doktorsexamen offentligen försvaras i Berzeliussalen, Hälsouniversitetet i Linköping, onsdagen den 25 februari 1998, kl 13.00. Fakultetsopponent Docent Jan Lötvall, Klinisk Farmakologi Sahlgrenska sjukhuset, Göteborg.

ABSTRACT

Asthma is one of the commonest diseases in industrialized countries. The cause and mechanisms of the disorder are still not fully understood, although it is known that inflammation in the airways plays an important role. Inflammatory mediators, e.g. leukotrienes, prostaglandins, histamine and bradykinin, are all possible actors in the asthmatic condition. Moreover, disturbance in the neurogenic system has been discussed: the cholinergic, adrenergic, and nonadrenergic noncholinergic systems may influence the airway tone. Structural changes in the airways of asthmatics, e.g. epithelial damage, have also been observed. The consequence of epithelial damage is not fully understood, but it is clear that the epithelial layer can act as a physical and metabolic barrier.

In the present research, we developed an in vitro model for determination of airway smooth muscle tension and concomitant mediator release in guinea pig airways. This method also allows manipulation of the airway epithelium. We found the condition of the airway epithelium to be of great significance for smooth muscle response and mediator release. An intact epithelium acted as a powerful barrier; removal of the epithelium resulted in increased responses to histamine, acetylcholine and potassium ions. An intact epithelial layer was also important for leukotriene and prostaglandin production, whereas in the absence of epithelium, antigen-induced contractions were almost completely dependent on histamine.

Sensory nerve activation provoked by electrical field stimulation (EFS), capsaicin (CAP) and antigen-induced mediators was investigated by analyzing the amount of neurokinin A-like immunoreactivity (NKA-LI). Multiple agents were shown to regulate this release. EFS-induced outflow of NKA-LI was powerfully decreased by morphine, and this reduction was not reversed by naloxone. In contrast, the inhibition obtained upon CAP-challenge was reversible. These results may imply that EFS also activates endogenous inhibitory systems.

Antigen challenge of epithelial-denuded bronchial tube preparations resulted in contractions and concomitant release of histamine and tachykinins. Exposure to pyrilamine (a histamine H1 receptor antagonist) and icatibant (a bradykinin B2 receptor antagonist) markedly depressed of NKA-LI outflow. Furthermore, pyrilamine significantly reduced the basal outflow of NKA-LI and antigen-induced contractions, while icatibant did not. These results show that, among the mediators released in response to antigen-challenge, histamine and bradykinin are able to modulate both the outflow of tachykinins and contractile responses.

The long-acting ß2 receptor agonist formoterol was characterized with regard to relaxing properties and effects on tachykinin and histamine release. The RR enantiomer was most potent in relaxing tracheal preparations, followed by racemic and SS-formoterol. Formoterol also reduced the antigen-induced outflow of NKA-LI. RR-formoterol also lowered both CAP- and EFS-induced NKA-LI outflow but not histamine release. These results indicate that, in addition to its ability to directly relax smooth muscle, formoterol may decrease the responses of airway tissue to antigen by inhibiting mediator release from sensory neurons, probably through direct interaction with sensory neurones.

In summary, we have developed a method for determination of epithelial influence, mediator release and smooth muscle contraction in guinea pig airways. We have shown that antigen-challenge release inflammatory mediators and activates sensory neurons. Both histamine and bradykinin are involved in the regulation of the tachykinin release. It was also shown that formoterol reduced NKA-LI outflow.

Keywords: airway obstruction, antigen, capsaicin, epithelium, inflammatory mediators, sensory neurons, tube preparation, tachykinins, formoterol, histamine, presynaptic inhibition, in vitro, guinea pig.

Division of Pharmacology, Department of Medicine and Care, Faculty of Health Sciences,
Linköping University, S-581 85 Linköping, Sweden
Linköping 1998

ISBN 91-7219-092-2 ISSN 0345-0082