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

Ting Wang, Christine Gross, Ankit A. Desai, Evgeny Alexandrovich Zemskov, Xiaomin Wu, Alexander N. Garcia, Jeffrey R. Jacobson, Jason X.J. Yuan, Joe G.N. Garcia, Stephen Matthew Black

Research output: Contribution to journalReview article

25 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)L452-L476
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume312
Issue number4
DOIs
Publication statusPublished - Apr 2017

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Keywords

  • ARDS
  • Acute lung injury
  • Endothelial cell barrier dysfunction
  • Inflammation
  • Mechanical forces
  • Transcriptional regulation
  • VILI

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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