Variable ventilation (VV) is a novel strategy of ventilatory support that utilizes random variations in the delivered tidal volume (V_T) to improve lung function. Since the stretch pattern during VV has been shown to increase surfactant release both in animals and cell culture, we hypothesized that there were combinations of PEEP and V_T during VV that led to improved alveolar recruitment compared to conventional mechanical ventilation (CV). To test this hypothesis, we developed a computational model of stretch-induced surfactant release combined with abnormal alveolar mechanics of the injured lung under mechanical ventilation. We modeled the lung as a set of distinct acini with independent surfactant secretion and thus pressure-volume relationships. The rate of surfactant secretion was modulated by the stretch magnitude that an alveolus experienced per breath. Mechanical ventilation was simulated by delivering a prescribed V_T at each breath. The fractional V_T that each acinus received depended on its local compliance relative to the total system compliance. Regional variability in V_T thus developed through feedback between stretch and surfactant release and coupling of regional V_T to ventilator settings. The model allowed us to simulate patient-ventilator interactions over a wide range of PEEPs and V_Ts during CV and VV. Full recruitment was achieved through VV at a lower PEEP than required for CV. During VV, the acini were maintained under non-equilibrium steady-state conditions with breath-by-breath fluctuations of regional V_T. In CV, alveolar injury was prevented with high-PEEP-low-V_T or low-PEEP-high-V_Tcombinations. In contrast, one contiguous region of PEEP-V_T combinations allowed for full recruitment without overdistention during VV. We found that maintaining epithelial cell stretch above a critical threshold with either PEEP or V_T may help stabilize the injured lung. These resultsdemonstrate the significance of patient-ventilator coupling through the influence of cellular stretch-induced surfactant release on the whole lung stability.