Determinants of plasma membrane wounding by deforming stress

Richard A. Oeckler, Won Yeon Lee, Mun Gi Park, Othmar Kofler, Deborah L. Rasmussen, Heung Bum Lee, Hewan Belete, Bruce J. Walters, Randolph W. Stroetz, Rolf D. Hubmayr

Research output: Contribution to journalArticle

31 Scopus citations

Abstract

Once excess liquid gains access to air spaces of an injured lung, the act of breathing creates and destroys foam and thereby contributes to the wounding of epithelial cells by interfacial stress. Since cells are not elastic continua, but rather complex network structures composed of solid as well as liquid elements, we hypothesize that plasma membrane (PM) wounding is preceded by a phase separation, which results in blebbing. We postulate that interventions such as a hypertonic treatment increase adhesive PM-cytoskeletal (CSK) interactions, thereby preventing blebbing as well as PM wounds. We formed PM tethers in alveolar epithelial cells and fibroblasts and measured their retractive force as readout of PM-CSK adhesive interactions using optical tweezers. A 50-mOsm increase in media osmolarity consistently increased the tether retractive force in epithelial cells but lowered it in fibroblasts. The osmo-response was abolished by pretreatment with latrunculin, cytochalasin D, and calcium chelation. Epithelial cells and fibroblasts were exposed to interfacial stress in a microchannel, and the fraction of wounded cells were measured. Interventions that increased PM-CSK adhesive interactions prevented blebbing and were cytoprotective regardless of cell type. Finally, we exposed ex vivo perfused rat lungs to injurious mechanical ventilation and showed that hypertonic conditioning reduced the number of wounded subpleural alveolus resident cells to baseline levels. Our observations support the hypothesis that PM-CSK adhesive interactions are important determinants of the cellular response to deforming stress and pave the way for preclinical efficacy trials of hypertonic treatment in experimental models of acute lung injury.

Original languageEnglish (US)
Pages (from-to)L826-L833
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume299
Issue number6
DOIs
StatePublished - Dec 2010

Keywords

  • Acute lung injury
  • Alveolar epithelial cell
  • Cytoprotection
  • Interfacial stress
  • Osmotic response

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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    Oeckler, R. A., Lee, W. Y., Park, M. G., Kofler, O., Rasmussen, D. L., Lee, H. B., Belete, H., Walters, B. J., Stroetz, R. W., & Hubmayr, R. D. (2010). Determinants of plasma membrane wounding by deforming stress. American Journal of Physiology - Lung Cellular and Molecular Physiology, 299(6), L826-L833. https://doi.org/10.1152/ajplung.00217.2010