Biology Reference
In-Depth Information
changes in conductance and resistance of airways could be calculated. In fact,
a prevention or protection against bronchoconstriction was measured assuming
that this protection translates to improvement of FEV1 in asthma.
Anaesthesia had two clear disadvantages: (1) a depressant effect on respiration
and (2) the necessity to dose by the parenteral route and not by oral administration.
Therefore, new models with conscious animals needed to be established. With
a non-invasive, thoracographic technique, (1) the change of respiratory rate, (2)
the peak flow and (3) the time of onset of dyspnea were recorded (Kilian et al.
1989
).
The tool was a probe which was placed around the thorax of the animal (a mercury-
in-rubber strain gauge) which by measuring movements of the thorax, was useful in
detecting (1) breathing pattern, (2) breathing frequency and (3) coughs. More
quantitative, but for routine purposes less suitable, methods were “whole-body”
and “half-body” plethysmography with conscious animals mimicking the principle
of body plethysmography in the clinics. These methods recorded specific airway
resistance calculated from the phase shift between thorax and nasal flow curves.
These methods and their variants are described in detail by Underwood et al. (
1993
).
An asthma attack in patients and in animal models was separated into an early
(EAR) and late asthmatic reaction (LAR). EAR represented the dyspnoea induced
by bronchoconstriction, which was related to the mediators histamine and LTC4
released from mast cells immediately after allergen contact. LAR started 4-6 h after
the EAR, lasted for up to 24 h and was followed by hyper-reactivity of the airways
(Cockroft
1983
). Hyper-reactivity represented an exaggerated bronchoconstrictor
response to a variety of stimuli such as histamine, adenosine, carbachol, exercise or
cold air, which appeared to be linked with perennial asthma but apparently were not
the consequence of acute contact with allergen. In 1983, J Morley had discovered
that inhalation of platelet-activating factor (PAF) could induce hyper-reactivity in
normal, non-sensitised guinea pigs. In the “pre-sensitisation” time period, this
finding was the basis for the experimental option to assess hyper-reactivity and,
in addition, in a conceptual way was the basis for the transient hypothesis that
platelets might be important cellular players in mucosal inflammation and airway
hyper-reactivity (Morley et al.
1984
). Thus, PAF-induced bronchial hyper-reactivity
of guinea pigs became an established method (Reaburn et al.
1994
). Hyper-reactivity
was tested by obtaining a dose-response curve for carbachol or histamine in the
absence or presence of drugs and the shift of the dose-response curves to higher
(less sensitive) values was given as PC20 defined as “provocative concentration to
reduce FEV1 by 20%” (Lotvall et al.
1998
; Hannon et al.
2001
).
In parallel, aiming at the allergic, immunologic feature of the disease, a sensi-
tisation procedure with OVA was developed and sensitised guinea pigs became the
standard model for investigation of allergic mechanisms (Andersson
1980
). In
sensitised guinea pigs, it occurred that adenosine became a bronchoconstrictor
agonist and evoked hyperreactivity versus other contracting agents which was in
line with the exchanged role of adenosine in human asthma (Cushley and Holgate
1985
). Thus, hyper-reactivity could now be established by adenosine treatment and
the shift of PC20 for methacholine was experimentally accessible (Thorne and
Broadley
1994
).
