The study of the biomechanical behavior of trachea and first bronchial generations is crucial in order to understand the effects exerted by a mechanical ventilator, since these airways represent the biological interface between the patient and the device. In this view, analyzing the central airways deformation, with quantification of the stress and strain originated in the biological structure may shed light on the mechanical aspects of possible tissue injury induced by the ventilation treatment. This is particularly important where total liquid ventilation (TLV) is concerned, since pressure dynamics in the central airways are quite different between TLV and conventional mechanical gas ventilation. To increase the knowledge of airway behavior during TLV, computer tomography (CT) scans were performed on New Zealand rabbits and preterm lambs to analyze airway deformation at the carinal level during TLV performed at different airway pressures, particularly during expiration. To deepen the analyses of the biomechanical airway behavior, a three-dimensional parametric computational model of the trachea, carina and first bronchi was developed to perform structural analyses (ABAQUS Standard version 6.4). The expiratory phase was simulated by means of fluid-dynamics analysis (Fluent 6.1), in order to determine shear stress values on the inner walls of the tracheal bifurcation, at different transmural pressures. Part of this research project, performed in cooperation with the University of Michigan research group, was aimed at evaluating the potential damage on the respiratory system due to collapse phenomena that might occur during expiration. In vivo tests were performed on 32 New Zealand rabbits, divided into 4 groups treated with different ventilation strategies (conventional gas ventilation, TLV, TLV with mild collapse induction, TLV with severe collapse induction). CT scans showed that airway narrowing during breathing performed in optimal pressure conditions (tracheal pressure (Ptrac) range 10 to +20 cmH2O) was minimal, while a significant lumen reduction occurred during collapse (Ptrac < –20 cmH2O), particularly in preterm lambs, whose highly compliant airways were almost completely occluded. This study confirmed the location of airway collapse and made it possible to quantify airway occlusion. The results of the structural analysis confirm that bifurcation partially occludes when the value of transmural pressure in the caudal region of the trachea falls below the negative threshold of -15 cmH2O. Bifurcation collapse becomes critical at pressure values around -30 cmH2O. However, even at the lowest pressure set in the analysis, equal to -60 cmH2O (pressure rarely reached during standard conditions of TLV), the occlusion is not complete and PFC flow is still possible. Histological analysis of lung parenchyma and airways performed to evaluate the damage potentially induced by repeated airway collapses showed minimal inflammatory response and no significant statistical difference between the groups ventilated with different strategies. The analysis of hemodynamic and gas exchange values showed that airway collapse does not affect lung and heart functionality. The developed computational model can properly reproduce the behavior of tracheae and principal bronchi during the respiratory cycle: the deformed shapes of model lumen are similar to the CT images, taken on the airways of the ventilated premature lambs, at the same pressure. As a result of the structural analysis, it can be asserted that the shear stress values rise with an increase in bifurcation collapse: since the expiratory flow rate is equal, the reduction of the cross section causes greater velocity gradients and consequently higher shear stress values on the internal walls. However, moderate shear stress (<120 Pa) was reached even at the worst airway collapse condition. The results of the in vivo study seem to confirm that the TLV treatment does not induce lung injury, even when performed in non-optimal conditions (i.e., when airway collapses occur). The outcomes of this study, coupled with work on TLV-ventilator development, PFC distribution and delivery, and gas exchange improvement, represent a necessary and important pre-clinical step in TLV development.