Pathologic mechanical stress and endotoxin exposure increases lung endothelial microparticle shedding

Am J Respir Cell Mol Biol. 2015 Feb;52(2):193-204. doi: 10.1165/rcmb.2013-0347OC.


Acute lung injury (ALI) results from infectious challenges and from pathologic lung distention produced by excessive tidal volume delivered during mechanical ventilation (ventilator-induced lung injury [VILI]) and is characterized by extensive alveolar and vascular dysfunction. Identification of novel ALI therapies is hampered by the lack of effective ALI/VILI biomarkers. We explored endothelial cell (EC)-derived microparticles (EMPs) (0.1-1 μm) as potentially important markers and potential mediators of lung vascular injury in preclinical models of ALI and VILI. We characterized EMPs (annexin V and CD31 immunoreactivity) produced from human lung ECs exposed to physiologic or pathologic mechanical stress (5 or 18% cyclic stretch [CS]) or to endotoxin (LPS). EC exposure to 18% CS or to LPS resulted in increased EMP shedding compared with static cells (∼ 4-fold and ∼ 2.5-fold increases, respectively). Proteomic analysis revealed unique 18% CS-derived (n = 10) and LPS-derived EMP proteins (n = 43). VILI-challenged mice (40 ml/kg, 4 h) exhibited increased plasma and bronchoalveolar lavage CD62E (E-selectin)-positive MPs compared with control mice. Finally, mice receiving intratracheal instillation of 18% CS-derived EMPs displayed significant lung inflammation and injury. These findings indicate that ALI/VILI-producing stimuli induce significant shedding of distinct EMP populations that may serve as potential ALI biomarkers and contribute to the severity of lung injury.

Keywords: LPS; cyclic stretch; microparticles; proteomics; ventilator-induced lung injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Lung Injury / drug therapy*
  • Acute Lung Injury / metabolism
  • Acute Lung Injury / pathology
  • Animals
  • Cell-Derived Microparticles / drug effects*
  • Cell-Derived Microparticles / pathology
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells / drug effects*
  • Endothelial Cells / metabolism
  • Endothelial Cells / pathology
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / pathology
  • Endotoxins / pharmacology*
  • Humans
  • Lipopolysaccharides / pharmacology
  • Male
  • Mice, Inbred C57BL
  • Pneumonia / chemically induced
  • Pneumonia / metabolism
  • Pneumonia / pathology
  • Stress, Mechanical*
  • Ventilator-Induced Lung Injury / drug therapy*
  • Ventilator-Induced Lung Injury / metabolism
  • Ventilator-Induced Lung Injury / pathology


  • Endotoxins
  • Lipopolysaccharides