Am. J. Respir. Cell Mol. Biol., Volume 25, Number 5, November, 2001 584-591

Role of Stretch on Tight Junction Structure in Alveolar Epithelial Cells

Kenneth J. Cavanaugh Jr., Jane Oswari, and Susan S. Margulies

Department of Bioengineering, University of Pennsylvania, Philadelphia, Pennsylvania

Previous studies have demonstrated that high tidal volumes can cause interstitial and alveolar edema, with degradation of pulmonary epithelial barrier integrity. Separate studies have shown that F-actin disruption and decreased intracellular ATP (ATP_i) levels in the nonpulmonary epithelium can increase tight junction (TJ) permeability. We hypothesized that large epithelial stretch perturbs ATP_i and actin architecture, each of which adversely affects TJ structure, and thus increases TJ permeability. Primary alveolar epithelial cells were subjected to a uniform 25% or 37% change in surface area (SA), cyclic biaxial stretch (15 cycles/min) for 1 h, or treated with either glycolytic metabolic inhibitors or cytoskeletal disrupting agents. Unstretched, untreated cells served as controls. Changes in the TJ proteins occludin and ZO-1 were determined by immunocytochemical evaluation. A stretch amplitude of 25% SA did not produce any significant cytologic changes compared with controls, but an amplitude of 37% SA stretch resulted in significant decreases in the intensity of the peripheral occludin band, the degree of cell-cell attachment (CCA), and total cellular occludin content. ATP depletion significantly diminished the occludin band intensity and decreased CCA. Actin disruption did not affect TJ protein band intensities (although the occludin distribution became punctate) but altered CCA. Untreated cells stretched cyclically at 25% or 50% SA for 1 h had significantly decreased ATP_i compared with unstretched controls. These results suggest that stretch-induced ATP_i reduction and actin perturbation disrupt TJ structure and CCA, which may lead to the alveolar flooding associated with high tidal volumes.

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