Institutet för miljömedicin (IMM) / Institute of Enviromental Medicine
Abstract
Asthma means difficulty in breathing and is described as a chronic,
inflammatory disorder that produces narrowing of the lower respiratory
tract. The allergen-induced asthmatic bronchoconstriction is primarily
caused by an IgE-mediated release of the mast cell mediators, histamine
and eicosanoids (leukotrienes and prostanoids). Asthmatics have elevated
levels of nitric oxide (NO) in the exhaled air, which been proposed as a
sign of airway inflammation. In the airways, mast cells represent a major
source of NO. This formed NO may act in an autocrine fashion to suppress
mast cell function, including release of histamine and leukotriene
synthesis, and thereby be a regulator of allergen-induced responses.
Nevertheless, the function of NO in the peripheral lung is not clear.
The aim of this thesis was therefore to establish the role of nitric
oxide and eicosanoids during early allergic airway responses in the
peripheral lung. Antigen-induced contractions to the allergen ovalbumin
were studied in the lung parenchyma obtained from actively sensitized
guinea pigs, an in vitro-model for mast cell driven antigen-induced
contractions. The peripheral lung is a complex tissue with airway smooth
muscle, bronchioles, vessels and connective tissue. To further understand
and characterize the contractile responses obtained to allergen or
agonists in lung parenchymal tissue, studies in guinea pig precision cut
lung slices (GP PCLS) were established and performed. Another aim of this
thesis was also to compare species differences during the early allergic
airway response in the PCLS.
Inhibition of nitric oxide synthase (NOS) enhanced the contractions to
cumulative doses of ovalbumin, whereas addition of the different NO
donors SNP and NCX 2057 attenuated the antigen-induced contractions. The
action of NO was however not relaxation of airway smooth muscle, since NO
potently dilated precontracted vascular preparations and weakly relaxed
precontracted tracheal rings, while there was no effect on precontracted
GPLP. Instead, NO act as inhibitor of allergen-induced mediator release
in the peripheral lung. Inhibition of endogenous NO increased the release
of leukotrienes, whereas SNP and NCX 2057 distinctly inhibited the
release of histamine or leukotrienes during antigen challenge. In
conclusion, the findings support that endogenous NO has a protective role
in the peripheral lung as a beneficial immunomodulator of the early
allergic airway response. The findings also indicate that different NO
donors may have selective and protective anti-inflammatory effects in the
peripheral lung tissue.
The GP PCLS was established and represents now a new in vitro model to
simultaneously measure airway and vascular responses under cell culture
conditions. The study showed that the pharmacology of the guinea pig PCLS
most closely resembled that of the corresponding human tissues. In guinea
pigs and humans, leukotrienes and prostanoids were primary mediators of
the antigen-induced bronchoconstriction. In contrast, the contractile
response to antigen in rat PCLS was mainly mediated by serotonin and
modulated by locally formed prostanoids, in particular COX-2 derived
PGE2, acting at EP1 receptors. Thus, mechanisms by which eicosanoids
contribute to the early allergic airway response differ among species
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