Die Dozenten der Informatik-Institute der Technischen Universität Braunschweig laden im Rahmen des Informatik-Kolloquiums zu folgendem Vortrag ein:
Srboljub M. Mijailovich, Ph.D., Harvard School of Public Health: Molecular Origins of Airway Narrowing: Multiscle Model Predictions of Hyperresponsiveness in Asthmatics
Beginn: 22.10.2009, 10:00 Uhr Ort: TU Braunschweig, Gauß-IT-Zentrum, Hans-Sommer-Str. 65, Seminarraum 012 Webseite: http://www.ibr.cs.tu-bs.de/cal/kolloq/2009-10-22-mijailovich.html Kontakt: Prof. Hermann G. Matthies, PhD
We have developed a theoretical multiscale model to quantify how alterations in the cross-bridge kinetics of airway smooth muscle (ASM) and in the airway wall remodeling affect the symptoms of asthma and chronic obstructive pulmonary disease (COPD). By taking into account the coupling between ASM contraction and the dynamics of breathing, the new model is able to predict the hyperreactivity of the asthmatic airways and their hypersensitivity to increasing doses of contractile agents. The latter could not be reproduced by previous models that considered static equilibrium between the isometric ASM force and the mean transpulmonary pressure.
In the presented model the airway caliber – proportional to the ASM length – is dynamically determined from the instantaneous balance between airway wall reaction force (AWRF) and the ASM contractile force. The AWRF is derived from transmural pressure across the airway wall and the forces of parenchymal tethering: it is computed from the elasticity and geometry of the airway wall, the tethering of the airway to the lung parenchyma, and the state of lung inflation. The resulting force is equivalent to an instantaneous load acting on the ASM in situ. This force depends on the transpulmonary pressure variation and the pressure drop along the airway tree during breathing. The ASM contractile force and length are determined using Mijailovich’s molecular model of smooth muscle contraction and regulation, based on the perturbed equilibria of myosin binding. The instantaneous airway luminal area and resistance are obtained from the ASM length for each airway generation in Weibel’s bronchial tree. The pressure drop along the tree is computed from the resistance and the instantaneous flow rate. The calculations include the effect of deep inspirations (DI) superimposed over quiet tidal breathing for normal, COPD, and asthmatic airways.
Our results show that at low doses of histamine, ASM reaches dynamical equilibrium at long lengths, and the airways are completely open and compliant. However, at histamine doses above a “critical” value, the ASM drastically shortens, and the airways are severely constricted and stiff. In COPD and asthmatic airways the critical dose is significantly lower than in normal airways; above this dose the degree of ASM shortening, and therefore airway constriction, are both significantly greater than in normal airways. In this case, DI may not be sufficient to open the asthmatic airways. The agreement between the model predictions and clinical observations suggests that both the hyperreactivity and hypersensitivity observed in asthmatic and COPD airways can be explained by a single mechanism – perturbed equilibria of myosin binding.