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Effect of Tiotropium on in vivo and ex vivo lung function in a rat model of bronchoconstriction

: Seehase, Sophie

American Journal of Respiratory and Critical Care Medicine 185 (2012), Abstract A3586
ISSN: 1073-449X
ISSN: 0003-0805
ISSN: 1535-4970
American Thoracic Society (ATS International Conference) <2012, San Francisco/Calif.>
Fraunhofer ITEM ()

Rationale: Precision cut lung slices (PCLS) display a convenient ex vivo model closely resembling morphology and functionality of the respiratory tract. Furthermore, PCLS allow the investigation of airway narrowing - a distinct symptom in asthma - under nearly identical experimental conditions by requiring only a small number of animals. In the present study, the effect of the bronchodilator tiotropium on acetylcholine induced bronchoconstriction was evaluated in rat PCLS. The results were correlated with in vivo experiments.
Methods: For preparation of PCLS, lungs of Brown Norway rats were removed after euthanasia, filled with agarose, and solidified on ice. Tissue cores with a centered airway were prepared and cut into PCLS with a microtome. PCLS were stimulated with increasing concentrations of acetylcholine. In addition, pre-incubation with tiotropium was performed. Half maximal effective concentrations (EC50) were calculated and compared. For in vivo measurements, Brown Norway rats were anesthetized and orotracheally intubated to measure lung resistance (RL) and dynamic compliance (Cdyn). Subsequently, inhalational acetylcholine (ACh) provocation was performed. In addition, rats were treated intratracheally with 1 µg/kg tiotropium 45 min before provocation.
Results: Acetylcholine induced bronchoconstriction in rat PCLS exhibiting an EC50 of 7.5 µM. Pre-incubation of PCLS with tiotropium inhibited acetylcholine-induced bronchoconstriction completely. In in vivo experiments rats showed a marked ACh-induced bronchoconstriction quantified as a 279% increase in RL above baseline which was nearly totally inhibited by tiotropium treatment (by 97%).
Conclusions: A strong inhibitory effect of tiotropium has been shown in vivo by means of invasive lung function measurement as well as in vitro by means of PCLS technique. Thus, PCLS are a promising model to study airway narrowing and therapeutical intervention ex vivo.