Background: We aim to investigate the effects of preconditioning of physiological cyclic stretch on the alveolar epithelial cell apoptosis induced by pathologically mechanical stretch and barrier dysfunction and how these effects are linked to differential expression of small GTPases Rac and Rho mRNA. Methods: Pulmonary alveolar epithelial cells were subjected to different treatments of cyclic stretch (CS) at 5% and 20% elongation, respectively. Cells maintained in normal cell culture were used as negative control. On the other hand, cell apoptosis and Rac/Rho activities in cells with or without preconditioning of physiologically relevant magnitudes of CS (5% CS) with different durations (0, 15, 30, 60 and 120 min) in prior to 6-h treatment with pathological CS stimulation (20% CS) were compared and measured. Results: Pathological CS could cause a significant increase in apoptosis rate, which is considered to be associated with the repression of Rac mRNA and activation of Rho mRNA. In contrast, physiological 5%-CS preconditioning suppressed cell apoptosis and induced nearly complete monolayer recovery with fewer actin stress fibers and paracellular gap formation. Consistent with differential effects on cell apoptosis and epithelial cell integrity, physiological CS preconditioning enhanced expression of Rac mRNA but inhibited Rho activation. Conclusions: Physiological CS preconditioning has an inhibitory effect on cell apoptosis while exerts a stimulatory impact on epithelial cell recovery via regulation of Rac and Rho activities. (C) 2014 Published by Elsevier Inc.