title: Endothelial cell signaling and ventilator-induced lung injury: molecular mechanisms, genomic analyses, and therapeutic targets.
abstract: Mechanical ventilation is a life-saving intervention in critically ill patients with respiratory failure due to acute respiratory distress syndrome (ARDS). Paradoxically, mechanical ventilation also creates excessive mechanical stress that directly augments lung injury, a syndrome known as ventilator-induced lung injury (VILI). The pathobiology of VILI and ARDS shares many inflammatory features including increases in lung vascular permeability due to loss of endothelial cell barrier integrity resulting in alveolar flooding. While there have been advances in the understanding of certain elements of VILI and ARDS pathobiology, such as defining the importance of lung inflammatory leukocyte infiltration and highly induced cytokine expression, a deep understanding of the initiating and regulatory pathways involved in these inflammatory responses remains poorly understood. Prevailing evidence indicates that loss of endothelial barrier function plays a primary role in the development of VILI and ARDS. Thus this review will focus on the latest knowledge related to1) the key role of the endothelium in the pathogenesis of VILI;2) the transcription factors that relay the effects of excessive mechanical stress in the endothelium;3) the mechanical stress-induced posttranslational modifications that influence key signaling pathways involved in VILI responses in the endothelium;4) the genetic and epigenetic regulation of key target genes in the endothelium that are involved in VILI responses; and5) the need for novel therapeutic strategies for VILI that can preserve endothelial barrier function.
authors.affiliation: Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona.
authors.forename: Ting
authors.initials: T
authors.lastname: Wang
authors.affiliation: Vascular Biology Center, Augusta University, Augusta, Georgia.
authors.forename: Christine
authors.initials: C
authors.lastname: Gross
authors.affiliation: Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona.
authors.forename: Ankit A
authors.initials: AA
authors.lastname: Desai
authors.affiliation: Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona.
authors.forename: Evgeny
authors.initials: E
authors.lastname: Zemskov
authors.affiliation: Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona.
authors.forename: Xiaomin
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pharmacology University of Illinois at Chicago, Chicago, Illinois; and.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Garcia
authors.affiliation: Department of Medicine, University of Illinois at Chicago, Chicago, Illinois.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Jacobson
authors.affiliation: Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona.
authors.forename: Jason X-J
authors.initials: JX
authors.lastname: Yuan
authors.affiliation: Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona.
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
authors.affiliation: Department of Medicine, The University of Arizona Health Sciences, Tucson, Arizona; steveblack@email.arizona.edu.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Black
mesh_terms: D000818:Animals; D042783:Endothelial Cells / Q000378:metabolism*; D023281:Genomics; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D015398:Signal Transduction; D013314:Stress, Mechanical; D055397:Ventilator-Induced Lung Injury / Q000235:genetics* / Q000628:therapy*
keywords: ARDS; VILI; acute lung injury; endothelial cell barrier dysfunction; inflammation; mechanical forces; transcriptional regulation