Endothelial cell signaling and ventilator-induced lung injury: molecular mechanisms, genomic analyses, and therapeutic targets.

TitleEndothelial cell signaling and ventilator-induced lung injury: molecular mechanisms, genomic analyses, and therapeutic targets.
Publication TypeJournal Article
Year of Publication2017
AuthorsWang T, Gross C, Desai AA, Zemskov E, Wu X, Garcia AN, Jacobson JR, Yuan JX-J, Garcia JGN, Black SM
JournalAm J Physiol Lung Cell Mol Physiol
Volume312
Issue4
PaginationL452-L476
Date Published2017 Apr 01
ISSN Number1522-1504
KeywordsAnimals, Endothelial Cells, Genomics, Humans, Models, Biological, Molecular Targeted Therapy, Signal Transduction, Stress, Mechanical, Ventilator-Induced Lung Injury
Abstract

<p>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 to 1) 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; and 5) the need for novel therapeutic strategies for VILI that can preserve endothelial barrier function.</p>

DOI10.1152/ajplung.00231.2016
Alternate JournalAm. J. Physiol. Lung Cell Mol. Physiol.
PubMed ID27979857
PubMed Central IDPMC5407098
Grant ListP01 HL101902 / HL / NHLBI NIH HHS / United States
R01 HL067841 / HL / NHLBI NIH HHS / United States
R35 HL135807 / HL / NHLBI NIH HHS / United States
R01 HL060190 / HL / NHLBI NIH HHS / United States
R01 HL136603 / HL / NHLBI NIH HHS / United States