Abstract
BackgroundAcute Respiratory Distress Syndrome (ARDS) is a condition that contributes to morbidity and mortality of critically ill patients. We investigated whether factors secreted by adipose stromal cells (ASC) into conditioned media (ASC-CM) will effectively decrease lung injury in the model of lipopolysaccharide (LPS)-induced ARDS.MethodsTo assess the effect of ASC-CM on ARDS indices, intravenous delivery of ASC and ASC-CM to C57Bl/6 mice was carried out 4 h after LPS oropharyngeal aspiration; Evans Blue Dye (EBD) was injected intravenously 1 h prior to animal sacrifice (48 h post-LPS). Lungs were either fixed for histopathology, or used to extract bronchoalveolar lavage fluid (BALF) or EBD. To assess the effect of ASC-CM on endothelial barrier function and apoptosis, human pulmonary artery endothelial cells were treated with ASC-CM for 48-72 h.ResultsASC-CM markedly reduced LPS-induced histopathologic changes of lung, protein extravasation into BALF, and suppressed the secretion of proinflammatory cytokines TNFα and IL6. White Blood Cells (WBC) from BALF of LPS-challenged mice receiving ASC-CM had decreased reactive oxygen species (ROS) generation compared to WBC from LPS-challenged mice receiving control media injection. Treatment of pulmonary endothelial monolayers with ASC-CM significantly suppressed H2O2-induced leakage of FITC dextran and changes in transendothelial resistance, as well as gap formation in endothelial monolayer. ASC-CM exposure reduced the percentage of endothelial cells expressing ICAM-1, and suppressed TNFα-induced expression of E-selectin and cleavage of caspase-3. ASC-CM reduced the endothelial level of pro-apoptotic protein Bim, but did not affect the level of Bcl-2, Bad, or Bad phosphorylation.ConclusionsFactors secreted by ASC efficiently reduce ARDS indices, endothelial barrier hyperpermeability, and activation of pro-inflammatory and pro-apoptotic pathways in endothelium.
Highlights
Acute Respiratory Distress Syndrome (ARDS) is a condition that contributes to morbidity and mortality of critically ill patients
Flow cytometric analyses of adipose stromal cells (ASC) surface markers Both murine and human ASC used in our study were produced by propagation of the cell fraction adherent to plastic under standard culture conditions. Murine ASC (mASC) and Human ASC (hASC) demonstrated typical size, spindle shape, and morphology in culture consistent with adipose stem cells. mASC as well as hASC were evaluated with respect to their surface marker phenotype at passage 3. mASC were positive for Sca-1, one of the markers routinely used to characterize mesenchymal stem cells of
Our study showed that a single administration of ASC conditioned media (ASC-CM) limited lung inflammatory histological changes, protein extravasation to airspaces, accumulation of inflammatory mediators TNFα and IL6 in bronchoalveolar lavage fluid (BALF), and the ability of BALF White Blood Cells (WBC) to generate reactive oxygen species (ROS)
Summary
Acute Respiratory Distress Syndrome (ARDS) is a condition that contributes to morbidity and mortality of critically ill patients. We investigated whether factors secreted by adipose stromal cells (ASC) into conditioned media (ASC-CM) will effectively decrease lung injury in the model of lipopolysaccharide (LPS)-induced ARDS. Initial studies exploring the effects of MSC on lung injury in rodents and explanted human lungs utilized bone marrow-derived mesenchymal stromal cells (MSC). These studies have shown that MSC suppressed lung injury in LPS- [9,10,11], Escherichia coli- [12], cecal ligation/puncture- [13,14], and bleomycin-induced [15] lung injury models. Similar to MSC, ASC are effective in inhibiting lung damage in ARDS in LPS- [17,18,19,20], cecal ligation/puncture- [21], ventilation- [22] and ischemia-reperfusion-induced [23] lung injury models
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