Human mesenchymal stem cells overexpressing the IL-33 antagonist soluble IL-1 receptor-like-1 attenuate endotoxin-induced acute lung injury

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) arecharacterizedbypulmonary edemaattributable toalveolar epithelial- interstitial-endothelial injury, associated with profound inflammation and respiratory dysfunction. The IL-33/IL-1 receptor-like-1 (ST2) axis plays a key role in the development of immune-inflammatory responses in the lung. Cell-based therapy has been recently proposed as an effective alternative for the treatment of ALI andARDS. Here,we engineered humanadipose tissue- derivedmesenchymal stem cells (hASCs) overexpressing soluble IL-1 receptor-like-1 (sST2), a decoy receptor for IL-33, in order to enhance their immunoregulatory and anti-inflammatory propertieswhen applied in amurine ALImodel.We administeredbothhASCs andhASC-sST2 systemically at 6hours after intranasal LPS instillation,whenpathological changeshad already occurred. Bioluminescence imaging, immunohistochemistry, andfocusedtranscriptionalprofilingconfirmedtheincreasedpresence of hASCs in the injured lungs and the activation of an immunoregulatory program (CXCR-4, tumor necrosis factor-stimulated gene 6 protein, and indoleamine 2,3-dioxygenase up-regulation) in these cells, 48 hours after endotoxinchallenge.Acomparative evaluationofhASCs and the actions of hASC-sST2 revealed that local sST2 overproduction by hASC-sST2 further prevented IL-33, Toll-like receptor-4, IL-1b, and IFN-γ induction, but increased IL-10 expression in the injured lungs. Thissynergycausedasubstantialdecreaseinlungairspaceinflammation and vascular leakage, characterized by significant reductions in protein content, differential neutrophil counts, and proinflammatory cytokine (TNF-α, IL-6, and macrophage inflammatory protein 2) concentrations in bronchoalveolar lavage fluid. In addition, hASC-sST2-treatedALI lungs showed preserved alveolar architecture, an absence of apoptosis, and minimal inflammatory cell infiltration. These results suggest that hASCs genetically engineered to produce sST2 could become a promising therapeutic strategy for ALI/ARDSmanagement. Copyright © 2013 by the American Thoracic Society.