PMID- 26592435 OWN - NLM STAT- MEDLINE DCOM- 20170920 LR - 20231111 IS - 1873-2380 (Electronic) IS - 0021-9290 (Print) IS - 0021-9290 (Linking) VI - 49 IP - 8 DP - 2016 May 24 TI - Superoxide mediates tight junction complex dissociation in cyclically stretched lung slices. PG - 1330-1335 LID - S0021-9290(15)00580-1 [pii] LID - 10.1016/j.jbiomech.2015.10.032 [doi] AB - We found that stretching Type I rat alveolar epithelial cell (RAEC) monolayers at magnitudes that correspond to high tidal-volume mechanical ventilation results in the production of reactive oxygen species, including nitric oxide and superoxide. Scavenging superoxide with Tiron eliminated the stretch-induced increase in cell monolayer permeability, and similar results were reported for rats ventilated at large tidal volumes, suggesting that oxidative stress plays an important role in barrier impairment in ventilator-induced lung injury associated with large stretch and tidal volumes. In this communication we show that mechanisms that involve oxidative injury are also present in a novel precision cut lung slices (PCLS) model under identical mechanical loads. PCLSs from healthy rats were stretched cyclically to 37% change in surface area for 1 hour. Superoxide was visualized using MitoSOX. To evaluate functional relationships, in separate stretch studies superoxide was scavenged using Tiron or mito-Tempo. PCLS and RAEC permeability was assessed as tight junction (TJ) protein (occludin, claudin-4 and claudin-7) dissociation from zona occludins-1 (ZO-1) via co-immunoprecipitation and Western blot, after 1h (PCLS) or 10min (RAEC) of stretch. Superoxide was increased significantly in PCLS, and Tiron and mito-Tempo dramatically attenuated the response, preventing claudin-4 and claudin-7 dissociation from ZO-1. Using a novel PCLS model for ventilator-induced lung injury studies, we have shown that uniform, biaxial, cyclic stretch generates ROS in the slices, and that superoxide scavenging that can protect the lung tissue under stretch conditions. We conclude that PCLS offer a valuable platform for investigating antioxidant treatments to prevent ventilation-induced lung injury. CI - Copyright (c) 2015 Elsevier Ltd. All rights reserved. FAU - Song, Min Jae AU - Song MJ AD - Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. FAU - Davidovich, Nurit AU - Davidovich N AD - Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. FAU - Lawrence, Gladys G AU - Lawrence GG AD - Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. FAU - Margulies, Susan S AU - Margulies SS AD - Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA. Electronic address: Margulies@seas.upenn.edu. LA - eng GR - R01 HL057204/HL/NHLBI NIH HHS/United States PT - Journal Article DEP - 20151111 PL - United States TA - J Biomech JT - Journal of biomechanics JID - 0157375 RN - 11062-77-4 (Superoxides) RN - 31C4KY9ESH (Nitric Oxide) SB - IM MH - Animals MH - Epithelial Cells/metabolism/*physiology MH - In Vitro Techniques MH - Nitric Oxide/metabolism MH - Oxidative Stress MH - Pulmonary Alveoli/cytology/physiology MH - Rats, Sprague-Dawley MH - Superoxides/*metabolism MH - Tight Junctions/*physiology MH - Ventilator-Induced Lung Injury/metabolism/*physiopathology PMC - PMC4864146 MID - NIHMS734227 OTO - NOTNLM OT - Lung injury OT - Oxidative stress OT - Permeability OT - Tight junctions EDAT- 2015/11/26 06:00 MHDA- 2017/09/21 06:00 PMCR- 2017/05/24 CRDT- 2015/11/24 06:00 PHST- 2015/06/24 00:00 [received] PHST- 2015/10/20 00:00 [revised] PHST- 2015/10/21 00:00 [accepted] PHST- 2015/11/24 06:00 [entrez] PHST- 2015/11/26 06:00 [pubmed] PHST- 2017/09/21 06:00 [medline] PHST- 2017/05/24 00:00 [pmc-release] AID - S0021-9290(15)00580-1 [pii] AID - 10.1016/j.jbiomech.2015.10.032 [doi] PST - ppublish SO - J Biomech. 2016 May 24;49(8):1330-1335. doi: 10.1016/j.jbiomech.2015.10.032. Epub 2015 Nov 11.