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The origin of frequency dependence of respiratory resistance has been explained by ventilation inhomogeneity; however, it is unclear which components in the respiratory system generate the frequency dependence. The author constructed a 4D pulmonary lobule model and analysed relationships between airflow rate, pressure and airway resistance by the use of computational fluid dynamics.The lobule model contained bifurcated bronchioles with two adjacent acini in which deformable inter-acinar septa and alveolar duct walls were designed. Constrictive conditions of respective bronchioles were designed, too. 4D finite element models for computational fluid dynamics were generated and airflow simulations were performed under moving boundary conditions of the arbitrary Lagrangean-Eulerean method. From the simulation results, airway resistances for various conditions were calculated.Tissue resistance emerged under the condition of different acinar pressures caused by unequal airway resistances. If the inter-acinar septum was shifted so as to cancel the pressure difference, the acinar pressures were equal in spite of unequal airway resistances, and hence, tissue resistances did not emerge. Therefore, the tissue resistance in the former case is thought to be an index of alveolar pressure inequality (which could be cancelled by mechanical interaction of lung parenchyma), rather than a material property of the tissue itself.Inequality of alveolar pressure decreases as the input oscillatory frequency increases. Therefore, frequency dependence of the respiratory resistance should be regarded as a conditional index of the alveolar pressure inequality caused by heterogeneous changes in the intra-pulmonary airway and/or the lung parenchyma.Airflow simulation with computational fluid dynamics by the use of a 4D lobule model revealed that frequency dependence of respiratory resistance measured by impulse oscillometry is an index of the alveolar pressure inequality caused by heterogeneous changes in the intra-pulmonary airway and/or the lung parenchyma.