title: Cyclic stretch-induced oxidative stress increases pulmonary alveolar epithelial permeability.
abstract: Mechanical ventilation with high tidal volumes has been associated with pulmonary alveolar flooding. Understanding the mechanisms underlying cyclic stretch-induced increases in alveolar epithelial permeability may be important in designing preventive measures for acute lung injury. In this work, we assessed whether cyclic stretch leads to the generation of reactive oxygen species in type I-like alveolar epithelial cells, which increase monolayer permeability via activation of NF-κB and extracellular signal-regulated kinase (ERK). We cyclically stretched type I-like rat primary alveolar epithelial cells at magnitudes of 12, 25, and 37% change in surface area (ΔSA) for 10 to 120 minutes. High levels of reactive oxygen species and of superoxide and NO specifically were detected in cells stretched at 37% ΔSA for 10 to 120 minutes. Exogenous superoxide and NO stimulation increased epithelial permeability in unstretched cells, which was preventable by the NF-κB inhibitor MG132. The cyclic stretch-induced increase in permeability was decreased by the superoxide scavenger tiron and by MG132. Furthermore, tiron had a dramatic protective effect on in vivo lung permeability under mechanical ventilation conditions. Cyclic stretch increased the activation of the NF-κB signaling pathway, which was significantly decreased with the ERK inhibitor U0126. Altogether, our in vitro and in vivo data demonstrate the sensitivity of permeability to stretch- and ventilation-induced superoxide production, suggesting that using antioxidants may be helpful in the prevention and treatment of ventilator-induced lung injury.
authors.affiliation: Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Nurit
authors.initials: N
authors.lastname: Davidovich
authors.forename: Brian C
authors.initials: BC
authors.lastname: DiPaolo
authors.forename: Gladys G
authors.initials: GG
authors.lastname: Lawrence
authors.forename: Peter
authors.initials: P
authors.lastname: Chhour
authors.forename: Nadir
authors.initials: N
authors.lastname: Yehya
authors.forename: Susan S
authors.initials: SS
authors.lastname: Margulies
mesh_terms: D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002463:Cell Membrane Permeability; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007976:Leupeptins / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D018384:Oxidative Stress; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012121:Respiration, Artificial / Q000009:adverse effects; D015398:Signal Transduction; D013481:Superoxides / Q000378:metabolism / Q000494:pharmacology; D055397:Ventilator-Induced Lung Injury / Q000517:prevention & control
chemical_list: D000975:Antioxidants; D002070:Butadienes; D007976:Leupeptins; D016328:NF-kappa B; D009570:Nitriles; C113580:U 0126; D013481:Superoxides; D009569:Nitric Oxide; D014013:1,2-Dihydroxybenzene-3,5-Disulfonic Acid Disodium Salt; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde