title: Shear stress-related mechanosignaling with lung ischemia: lessons from basic research can inform lung transplantation.
abstract: Cessation of blood flow represents a physical event that is sensed by the pulmonary endothelium leading to a signaling cascade that has been termed "mechanotransduction." This paradigm has clinical relevance for conditions such as pulmonary embolism, lung bypass surgery, and organ procurement and storage during lung transplantation. On the basis of our findings with stop of flow, we postulate that normal blood flow is "sensed" by the endothelium by virtue of its location at the interface of the blood and vessel wall and that this signal is necessary to maintain the endothelial cell membrane potential. Stop of flow is sensed by a "mechanosome" consisting of PECAM-VEGF receptor-VE cadherin that is located in the endothelial cell caveolae. Activation of the mechanosome results in endothelial cell membrane depolarization that in turn leads to activation of NADPH oxidase (NOX2) to generate reactive oxygen species (ROS). Endothelial depolarization additionally results in opening of T-type voltage-gated Ca(2+) channels, increased intracellular Ca(2+), and activation of nitric oxide (NO) synthase with resultant generation of NO. Increased NO causes vasodilatation whereas ROS provide a signal for neovascularization; however, with lung transplantation overproduction of ROS and NO can cause oxidative injury and/or activation of proteins that drive inflammation and cell death. Understanding the key events in the mechanosignaling cascade has important lessons for the design of strategies or interventions that may reduce injury during storage of donor lungs with the goal to increase the availability of lungs suitable for donation and thus improving access to lung transplantation.
authors.affiliation: Institute for Environmental Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennyslvania; shampac@mail.med.upenn.edu.
authors.forename: Shampa
authors.initials: S
authors.lastname: Chatterjee
authors.affiliation: Department of Surgery, SUNY Upstate Medical University, Syracuse, New York; and.
authors.forename: Gary F
authors.initials: GF
authors.lastname: Nieman
authors.affiliation: Pulmonary Allergy and Critical Care Division, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Christie
authors.affiliation: Institute for Environmental Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennyslvania;
authors.forename: Aron B
authors.initials: AB
authors.lastname: Fisher
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D020747:Calcium Channels, T-Type / Q000235:genetics / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism / Q000473:pathology; D015870:Gene Expression; D006801:Humans; D007511:Ischemia / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D008168:Lung / Q000098:blood supply* / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D016040:Lung Transplantation; D040542:Mechanotransduction, Cellular; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009569:Nitric Oxide / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000235:genetics / Q000378:metabolism; D013314:Stress, Mechanical
chemical_list: D015820:Cadherins; D020747:Calcium Channels, T-Type; D008562:Membrane Glycoproteins; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D017382:Reactive Oxygen Species; D009569:Nitric Oxide; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D040262:Receptors, Vascular Endothelial Growth Factor
keywords: EVLP; KATP channel; NADPH oxidase; ischemia-reperfusion; lung ischemia; lung perfusion and storage; lung transplantation; mechanotransduction; reactive oxygen species