MPS 11-10 Targeted Delivery of Rat Induced Pluripotent Stem Cell-Derived Endothelial Cells Overexpressing Interleukin-8 Receptors Attenuates Liposaccharide-Induced lung Injury

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Acute lung injury (ALI) and its more severe form acute respiratory distress syndrome (ARDS) are a leading cause of morbidity and mortality in critically ill patients. Despite decades of research, there is still no effective therapy for ALI/ARDS, and treatment options are largely limited to supportive care. Neutrophil-mediated inflammation and endothelial cell (EC) injury are unifying features of the pathogenesis of ALI/ARDS. Interleukin-8 (IL8) receptors IL8RA and IL8RB (ILRA/RB) on neutrophil membranes bind to IL8 with high affinity and play a critical role in neutrophil recruitment to sites of injury and/or inflammation. This study tested the hypothesis that administration of rat induced pluripotent stem (iPS) cell-derived ECs (iPS-ECs) overexpressing IL8RA/RB inhibits liposaccharide (LPS)-induced ALI.

Design and Method:

12-wk-old ovariectomized SD rats were divided into three groups and received intra-peritoneal (i.p.) injection of saline (Sham); LPS (Escherichia coli 026:B6, Sigma-Aldrich, 10 mg/kg, i.p.) followed by i.v. infusion of saline; iPS-ECs overexpressing IL8RA/RB (IL8RA/RB-iPS-EC, 1.5 x 106 cells/rat, 2 hrs post LPS), or iPS-ECs overexpressing Ad-Null vector (AdNull-iPS-EC, 1.5 x 106 cells/rat, 2hrs post LPS), respectively. 6 hrs after LPS treatment, pro-inflammatory cytokine/chemokine mRNA levels were measured by real-time, RT-PCR in total lung homogenates. Neutrophil infiltration was assessed by immunohistochemical staining. Pulmonary edema was assessed by wet to dry weight ratio and Evans blue staining.


Expression of mRNA for adhesion molecule [P-selectin, vascular cell adhesion molecule (VCAM)-1, and intercellular adhesion molecule (ICAM)-1], chemoattractant [cytokine-induced neutrophil chemoattractant (CINC)-2β and monocyte chemoattractant protein (MCP)-1], and pro-inflammatory cytokine [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] was markedly increased in lungs of LPS rats. Transfusion of IL8RA/RB-iPS-ECs significantly attenuated expression of the pro-inflammatory mediators (by 40–50%) in LPS-injured lungs. Transfusion of IL8RA/RB-ECs also significantly attenuated LPS-induced neutrophil infiltration, pulmonary edema and vascular permeability changes.


These provocative findings indicate that targeted delivery of iPS-ECs overexpressing IL8RA/RB protects against LPS-induced acute lung injury.

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