Pathologic Mechanical Stress and Endotoxin Exposure Increases Lung Endothelial Microparticle Shedding.

Acute lung injury (ALI) results from infectious challenges as well as pathologic lung distention produced by excessive tidal volume delivered during mechanical ventilation (ventilator-induced lung injury or VILI) and is characterized by extensive alveolar and vascular dysfunction. Identification of novel ALI therapies, however, 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 EC exposed to either physiologic or pathologic mechanical stress (5% or 18% cyclic stretch or CS) or to lipopolysaccharide (LPS). EC exposure to either 18% CS or to LPS resulted in increased EMP shedding compared to 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, 4h) exhibited increased plasma and BAL CD62E (E-selectin)-positive MPs compared to 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.