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Tubulin Acetylation and Histone Deacetylase 6 Activity in the Lung under Cyclic Load

¹ Division of Pulmonary and Critical Care Medicine, Northwestern University Medical School, Chicago, Illinois; ² Department of Bioengineering, Florida Gulf Coast University, Fort Myers, Florida; and ³ Department of Pediatrics, University of Rochester, Rochester, New York

Correspondence and requests for reprints should be addressed to David A. Dean, Ph.D., Department of Pediatrics, Box 850, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642. E-mail: david_dean{at}urmc.rochester.edu

Previous studies from our lab have demonstrated that upon exposure to physiologic levels of cyclic stretch, alveolar epithelial cells demonstrate a significant decrease in the amount of polymerized tubulin (Geiger et al., Gene Therapy 2006;13:725–731). However, not all microtubules are disassembled, although the mechanisms or implications of this were unknown. Using immunofluorescence microscopy, Western blotting, and immunohistochemistry approaches, we have compared the levels of acetylated tubulin in stretched and unstretched A549 cells and in murine lungs. In cultured cells exposed to cyclic stretch (10% change in basement membrane surface area at 0.25 Hz), nearly all of the remaining microtubules were acetylated, as demonstrated using immunofluorescence microscopy. In murine lungs ventilated for 20 minutes at 12 to 20 ml/kg followed by 48 hours of spontaneous breathing or for 3 hours at 16 to 40 ml/kg, levels of acetylated tubulin were increased in the peripheral lung. In both our in vitro and in vivo studies, we have found that mild to moderate levels of cyclic stretch significantly increases tubulin acetylation in a magnitude- and duration-dependent manner. This appears to be due to a decrease in histone deacetylase 6 activity (HDAC6), the major tubulin deacetylase. Since it has been previously shown that acetylated microtubules are positively correlated to a more stable population of microtubules, this result suggests that microtubule stability may be increased by cyclic stretch, and that tubulin acetylation is one way in which cells respond to changes in exogenous mechanical forces.

Key Words: microtubule • histone deacetylase 6 • acetylation • alveolar epithelium

CLINICAL RELEVANCE Prolonged and even short-term mechanical ventilation can cause profound changes in the alveolar epithelium. We show that stretch in cells and lungs increases in the numbers of stable, acetylated microtubules via inhibition of the HDAC6.