TISSUE NONLINEARITY AS A NOVEL MECHANISM FOR THE FREQUENCY DEPENDENCE OF RESPIRATORY RESISTANCE TO AIRFLOW IN DISEASE
RATIONALE: The frequency dependence of resistance, 𝑅(𝑓), is currently being used as a clinical measure, thought to assess small airway heterogeneity of the respiratory system. However, it also can arise from tissue viscoelasticity, upper airway shunt, and recently a novel mechanism due to time-variation in mechanical properties, but potential sources of this time variation such as from the nonlinear mechanical properties have not been investigated. METHODS: Here using measurements from lung tissue and analytical modeling using constant phase models amended with nonlinear tissue or pressure-volume mechanics, we investigated if the time-varying mechanics that can arise from tissue nonlinearities during stretch lead to increases in 𝑅(𝑓). We explored these models at different operating stretches or volumes with different stretch amplitudes and different degrees of nonlinearities. We also modeled the normal pressure-volume relationship as well as curves representative of fibrosis and emphysema. We also investigated if time-varying properties from ventilation or oscillometry due to the nonlinear pressure-volume relationship can also predict 𝑅(𝑓) and if it is increased in patients with lung transplants including patients with chronic lung allograft dysfunction. RESULTS AND DISCUSSION: We found that nonlinearity in tissue and the respiratory system could increase low-frequency resistance above the static model resistance and thus lead to 𝑅(𝑓) greater than predicted from the constant phase model. 𝑅(𝑓) increased more strongly with increases in mean stretch volume, amplitude, or the exponent of the nonlinearity. The increase in 𝑅(𝑓) was mechanistically related to the time variation of stiffness during oscillatory stretch or ventilation of the models. 𝑅(𝑓) was increased as much as 200% during modeled mechanical ventilation in the ventilation frequency range (0.2−5 𝐻𝑧), however, this effect was nearly absent during modeled oscillometry (5−37 𝐻𝑧). This can be largely attributed to the much smaller oscillation amplitude, and lack of any effects from the breathing motion in the oscillometry frequency range in our model. CONCLUSIONS: Nonlinearity in lung tissue or the pressure-volume curve during stretch or ventilation respectively, leads to time variations in mechanical properties that cause increases in low-frequency resistance and thus 𝑅(𝑓) larger than observed from tissue viscoelastic properties alone. Increases in nonlinearity can be a source of 𝑅(𝑓) not previously identified that may be important to the interpretation of the effects of lung disease on lung tissue mechanics and provides a novel mechanism for the origin of the 𝑅(𝑓) and its changes. While pressure-volume nonlinearity can strongly affect 𝑅(𝑓) determined during mechanical ventilation, measurements by oscillometry are likely not susceptible, although we did not model other sources of time variation such as flow limitation.