title: Influence of cytoskeletal structure and mechanics on epithelial cell injury during cyclic airway reopening.
abstract: Although patients with acute respiratory distress syndrome require mechanical ventilation, these ventilators often exacerbate the existing lung injury. For example, the cyclic closure and reopening of fluid-filled airways during ventilation can cause epithelial cell (EpC) necrosis and barrier disruption. Although much work has focused on minimizing the injurious mechanical forces generated during ventilation, an alternative approach is to make the EpC less susceptible to injury by altering the cell's intrinsic biomechanical/biostructural properties. In this study, we hypothesized that alterations in cytoskeletal structure and mechanics can be used to reduce the cell's susceptibility to injury during airway reopening. EpC were treated with jasplakinolide to stabilize actin filaments or latrunculin A to depolymerize actin and then exposed to cyclic airway reopening conditions at room temperature using a previously developed in vitro cell culture model. Actin stabilization did not affect cell viability but significantly improved cell adhesion primarily due to the development of more numerous focal adhesions. Surprisingly, actin depolymerization significantly improved both cell viability and cell adhesion but weakened focal adhesions. Optical tweezer based measurements of the EpC's micromechanical properties indicate that although latrunculin-treated cells are softer, they also have increased viscous damping properties. To further investigate the effect of "fluidization" on cell injury, experiments were also conducted at 37 degrees C. Although cells held at 37 degrees C exhibited no changes in cytoskeletal structure, they did exhibit increased viscous damping properties and improved cell viability. We conclude that fluidization of the actin cytoskeleton makes the EpC less susceptible to the injurious mechanical forces generated during cyclic airway reopening.
authors.affiliation: Mechanical Engineering and BioEngineering, Lehigh University, Bethlehem, PA, USA.
authors.forename: H C
authors.initials: HC
authors.lastname: Yalcin
authors.forename: K M
authors.initials: KM
authors.lastname: Hallow
authors.forename: J
authors.initials: J
authors.lastname: Wang
authors.forename: M T
authors.initials: MT
authors.lastname: Wei
authors.forename: H D
authors.initials: HD
authors.lastname: Ou-Yang
authors.forename: S N
authors.initials: SN
authors.lastname: Ghadiali
mesh_terms: D000199:Actins / Q000378:metabolism; D001696:Biomechanical Phenomena / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002448:Cell Adhesion / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism*; D047630:Depsipeptides / Q000494:pharmacology; D055119:Elastic Modulus / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008856:Microscopy, Fluorescence; D052898:Optical Tweezers; D013314:Stress, Mechanical; D013696:Temperature; D053778:Thiazolidines / Q000494:pharmacology; D016596:Vinculin / Q000378:metabolism
chemical_list: D000199:Actins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D047630:Depsipeptides; D053778:Thiazolidines; C057531:jasplakinolide; D016596:Vinculin; C037067:latrunculin A