title: Stretch increases alveolar epithelial permeability to uncharged micromolecules.
abstract: We measured stretch-induced changes in transepithelial permeability in vitro to uncharged tracers 1.5-5.5 A in radius to identify a critical stretch threshold associated with failure of the alveolar epithelial transport barrier. Cultured alveolar epithelial cells were subjected to a uniform cyclic (0.25 Hz) biaxial 12, 25, or 37% change in surface area (DeltaSA) for 1 h. Additional cells served as unstretched controls. Only 37% DeltaSA (100% total lung capacity) produced a significant increase in transepithelial tracer permeability, with the largest increases for bigger tracers. Using the permeability data, we modeled the epithelial permeability in each group as a population of small pores punctuated by occasional large pores. After 37% DeltaSA, increases in paracellular transport were correlated with increases in the radii of both pore populations. Inhibition of protein kinase C and tyrosine kinase activity during stretch did not affect the permeability of stretched cells. In contrast, chelating intracellular calcium and/or stabilizing F-actin during 37% DeltaSA stretch reduced but did not eliminate the stretch-induced increase in paracellular permeability. These results provide the first in vitro evidence that large magnitudes of stretch increase paracellular transport of micromolecules across the alveolar epithelium, partially mediated by intracellular signaling pathways. Our monolayer data are supported by whole lung permeability results, which also show an increase in alveolar permeability at high inflation volumes (20 ml/kg) at the same rate for both healthy and septic lungs.
authors.affiliation: Department of Bioengineering, 3320 Smith Walk, University of Pennsylvania, Philadelphia, 19104-6392, USA.
authors.forename: Kenneth J
authors.initials: KJ
authors.lastname: Cavanaugh
authors.forename: Taylor S
authors.initials: TS
authors.lastname: Cohen
authors.forename: Susan S
authors.initials: SS
authors.lastname: Margulies
mesh_terms: D000199:Actins / Q000378:metabolism; D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000737:chemistry / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D002614:Chelating Agents / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D047630:Depsipeptides / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D008168:Lung / Q000033:anatomy & histology / Q000502:physiology; D008297:Male; D010316:Particle Size; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020545:Respiratory Mucosa / Q000166:cytology*; D013314:Stress, Mechanical
chemical_list: D000199:Actins; D000596:Amino Acids; D015415:Biomarkers; D002614:Chelating Agents; D047630:Depsipeptides; C057531:jasplakinolide; C070379:1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid acetoxymethyl ester; D004533:Egtazic Acid; D011505:Protein-Tyrosine Kinases; D011493:Protein Kinase C; D002118:Calcium