Biology Reference
In-Depth Information
Another model was the “SRS-A-model” recording the LTC
4
-mediated contrac-
tion. Guinea pigs had to be pretreated with antihistamines and COX inhibitors in
order to dissect out the constriction due to LTC
4
. Furthermore, the isolated trachea
from sensitised guinea pigs served for in vitro experiments which predicted the
drug-sensitivity in the isolated organ model, and it was shown that the mucosa was
responsible for the reactivity towards OVA (Goldie et al.
1986
).
In 1988, the concept of asthma pathogenesis changed to the view that the disease
persists outside the acute episodes and that a continuous pulmonary inflammation
is the prerequisite of allergic attacks and hyperresponsiveness (Kay
1987
; Barnes
1989; Hargreave
1989
). Asthma was described as an “eosinophilic desquamative
bronchitis” and mechanistically a cellular hierarchy emerged with (1) dendritic
cells to recognise the antigens, (2) antigen-specific TH2 cells to release IL-5 and
IL-4 and to orchestrate the inflammation and finally (3) terminal effector cells such
as eosinophils, neutrophils and mast cells to release tissue-degrading enzymes,
ROS, cytokines and mediators.
Consequently, following these conceptual papers pulmonary inflammation was
measured in patients as well as in OVA-sensitised animal models by bronchoalveolar
lavage (BAL). Sensitised animals were treated with substance and 1 h later allergen
challenge was performed by inhalation. Lavages with buffer were performed at
various time points after challenge - and complex analyses - a fixed time point of
24 h was chosen to demonstrate inflammatory changes as well as drug-related
effects (Coyle et al.
1988
; Schudt et al.
1991a
,
b
,
c
; Underwood et al.
1993
). The
predominant use of guinea pigs had historical reasons since their allergic reactions
were mediated by IgE and histamine as it occurs in human. Unfortunately, guinea
pigs were highly susceptible to pneumonia and often blood and/or pulmonary
eosinophilia were observed without any specific reason. Rats, however, were used
for most other inflammatory models; pharmacokinetic and toxicological studies
were routinely performed in rats; hence, the use of laboratory animals in respiratory
research was shifted to rats (Hatzelmann et al.
1996b
).
Chronic asthma was characterised by remodelling of airways, by thickening of
the smooth muscle and the mucous layer which was due to increased cell mass and
edema. In mice, these long-term changes could be mirrored in a chronic asthma
model using OVA-sensitised mice exposed to aerosolised OVA at 3 days/week for
6 weeks. In the last 2 weeks, the drug was added daily and drug-induced changes of
(1) subepithelial collagenisation, (2) thickening of the airways, (3) goblet cell
hyperplasia and (4) TGFß accumulation were reported (Kumar et al.
2003
).
6.3 Zardaverine and Tolafentrine
Zardaverine was synthesised in 1984 and was determined to be a dual PDE inhibitor
with equivalent potency for PDE3 and PDE4 which translated to the cells and
isolated organs available at that time point (Tables
2
and
3
). Bronchoconstriction
in vivo was inhibited 100-fold more potently by zardaverine than by theophylline
