Regulation of experimentally induced airway obstruction
1998 (English)Doctoral thesis, comprehensive summary (Other academic)
Asthma is one of the commonest diseases in industrialized countries. The cause and mechanisms of !he disorder are still not fully unden;tood, al!hough it is known that inflammation in !he airways plays an important role. Inflammatory mediators, e.g. leukotrienes, prostaglandins, histamine and bradykinin, are all possible acton; in !he asthmatic condition. Moreover, disturbance in !he neurogenic system has been discussed: the cholinergic, adrenergic, and nonadrenergic noncholinergic systems may influence the airway tone. Structural changes in !he airways of as!hmatics, 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 detenninadon of airway smooth muscle tension and concomitant mediator release in guinea pig airways. This method also allows manipulation of the airway epithelium. We found !he condition of !he 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 !he 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 !he amount of neurokinin A-like immunoreactivity (NKA-Ll). Multiple agents were shown to regulate this release. EFSinduced outflow of NKA-LI was powerfully decreased by morphine, and !his reduction was not reversed by naloxone. In contrast, the inhibition obtained upon CAP-challenge was reven;ible. These results may imply !hat EFS also activates endugenous 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 H 1 receptor antagonist) and icatibant (a bradykinin B2 receptor antagonist) markedly depressed !he NKA-LI outflow. Furthermore, pyrilamine significantly reduced !he basal outflow of NKA-LI and antigen-induced contractions, while icatibant did not. These results show that, among !he 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 132 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 CAPand 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 inlluence, 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 tackykinin release. It was also shown that formoterol reduoed NKA-LI outflow.
Place, publisher, year, edition, pages
Linköping: Linköpings universitet , 1998. , 70 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 543
airway obstruction, antigen, capsaicin, epithelium, inflammatory mediators, sensory neurons, tube preparation, tachykinins, formoterol, histamine, presynaptic inhibition, in vitro, guinea pig
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-27515Local ID: 12171ISBN: 91-7219-092-2OAI: oai:DiVA.org:liu-27515DiVA: diva2:248067
1998-02-25, Berzeliussalen, Universitetssjukhuset, Linköping, 13:00 (Swedish)
Lötvall, Jan, Docent
Papers, included in the Ph.D. thesis, are not registered and included in the posts from 1999 and backwards.2009-10-082009-10-082012-11-09Bibliographically approved