Abstract 16371: Targeted Delivery of Pulmonary Arterial Endothelial Cells Overexpressing Interleukin-8 Receptors Attenuates Liposaccharide-induced Lung Injury
Background: 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/B) 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 pulmonary arterial ECs overexpressing IL8RA/B inhibits liposaccharide (LPS)-induced acute lung injury.
Methods and Results: 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; or LPS followed by i.v. transfusion of ECs overexpressing IL8RA/B (IL8RA/B-EC, 2hrs post LPS), respectively. 6 hrs after LPS treatment, pro-inflammatory cytokine/chemokine mRNA levels were measured by real-time, RT-PCR in homogenates of right lung. Neutrophil infiltration and lung injury were assessed by immunohistochemical staining and H&E staining in tissue sections of formalin-fixed, paraffin-embedded left lung. Expression of mRNA for adhesion molecule (P-selectin, vascular cell adhesion molecule-1, and intercellular adhesion molecule-1), chemoattractant (cytokine-induced neutrophil chemoattractant-2 beta and monocyte chemoattractant protein-1), and pro-inflammatory cytokine (interleukin-6 and tumor necrosis factor-alpha) was markedly increased in lungs of LPS rats. Transfusion of IL8RA/B-ECs significantly attenuated expression of the pro-inflammatory mediators (by 50% to 70%) in LPS-injured lungs. Transfusion of IL8RA/B-ECs also significantly attenuated LPS-induced neutrophil infiltration and lung injury response.
Conclusion: These provocative findings indicate that targeted delivery of ECs overexpressing IL8RA/B protects against LPS-induced acute lung injury.
Author Disclosures: D. Xing: None. S.S. Giordano: None. A. Gaggar: None. W. Feng: None. Y. Chen: None. J. Creighton: None. S. Oparil: None.
- © 2015 by American Heart Association, Inc.