Ventilator induced lung injury has been proposed as being caused by alveolar overdistention and/or repetitive closure and reopening of the small airways and alveoli. Here we investigate the possibility that during heterogeneous constriction, mechanical shear stress due to high airflow can increase to a dangerously high level that may be sufficient to cause injury/inflammation by damaging the epithelial cells during mechanical ventilation. We employed a novel anatomically consistent numerical model of the respiratory system, based on the Horsfield morphometric data set, and solved for the time evolution of pressure and flow distribution along the airway tree during mechanical ventilation. We simulated volume-controlled ventilation with constant flow during inspiration and passive expiration in two different conditions: baseline and highly heterogeneous constriction. The constriction was applied with two different strategies: establishing a simultaneous diameter reduction and length shortening or a simple diameter reduction. The time course of the distribution of shear stresses on airway walls was calculated and analyzed for airway generations ranging from the trachea to the acini. Our results indicate that 1) heterogeneous constriction can amplify the maximal values of shear stress up to 50 fold with peak values higher than 0.6 cmH₂O; 2) the highest shear stress is found in pathways constricted by 60-80%; 3) simultaneous diameter reduction and shortening further amplifies the shear stresses by 3-4 fold with shear stresses reaching 2 cmH₂O and 4) there is a range of airways (diameters from 0.6 to 0.3 mm at baseline) that appear to be at risk of very high shear stresses. We conclude that elevated airflow-related shear stress on the epithelial cell layer can occur during heterogeneous constriction, and conjecture that this may constitute a mechanism contributing to, or exacerbating, ventilator induced lung injury.