title: Pathologic mechanical stress and endotoxin exposure increases lung endothelial microparticle shedding.
abstract: 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.
authors.affiliation: 1 Division of Pulmonary, Critical Care, Sleep, and Allergy, Department of Medicine.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Letsiou
authors.forename: Saad
authors.initials: S
authors.lastname: Sammani
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.forename: Tong
authors.initials: T
authors.lastname: Zhou
authors.forename: Hector
authors.initials: H
authors.lastname: Quijada
authors.forename: Liliana
authors.initials: L
authors.lastname: Moreno-Vinasco
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dudek
authors.forename: Joe G N
authors.initials: JG
authors.lastname: Garcia
mesh_terms: D055371:Acute Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D055252:Cell-Derived Microparticles / Q000187:drug effects* / Q000473:pathology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D013314:Stress, Mechanical; D055397:Ventilator-Induced Lung Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology
chemical_list: D004731:Endotoxins; D008070:Lipopolysaccharides
keywords: LPS; cyclic stretch; microparticles; proteomics; ventilator-induced lung injury