作者: Goodwin, Andrew ; Fan, Hongkuan ; Halushka, Perry ; Zhang, Xian ; Zingarelli, Basilia ; Wang, Liping ; Argraves, Kelley ; Guo, Changrun ; Cook, James ; Buie, Joy N Jones

Endothelial cell (EC) dysfunction is a critical mediator of the acute respiratory distress syndrome (ARDS). Recent studies have demonstrated that stromal cell-derived factor 1α (SDF-1α) promotes EC barrier integrity. Our previous studies used a SDF-1α analogue CTCE-0214 (CTCE) in experimental sepsis and demonstrated that it attenuated vascular leak and modulated microRNA (miR) levels. We examined the hypothesis that CTCE improves EC function in lipopolysaccharide (LPS)-induced ARDS through increasing miR-126 expression. Human microvascular endothelial cells (HMVECs) were treated with thrombin to disrupt the EC integrity followed by incubation with CTCE or SDF-1α. Barrier function was determined by trans-endothelial electrical resistance assay. CTCE-induced alterations in miRNA expression and signaling pathways involved in barrier function were determined. Thrombin-induced vascular leak was abrogated by both CTCE and SDF-1α. CTCE also prevented thrombin-induced decreases of vascular endothelial (VE)-cadherin cell surface expression and expansion of the intercellular space. CTCE increased miR-126 levels and induced activation of AKT/Rac 1 signaling. Cotreatment with a miR-126 inhibitor blocked the protective effects of CTCE on AKT activation and endothelial permeability. In subsequent in vivo studies, ARDS was induced by intratracheal instillation of LPS. Intravenous injection of CTCE diminished the injury severity as evidenced by significant reductions in protein, immune cells, inflammatory cytokines and chemokines in the bronchoalveolar lavage fluid, increased miR-126 expression and decreased pulmonary vascular leak and alveolar edema. Taken together, our data show that CTCE improves endothelial barrier integrity through increased expression of miR-126 and activation of Rac 1 signaling and represents an important potential therapeutic strategy in ARDS.

2014-06-15·American Journal of Respiratory and Critical Care Medicine1区 · 医学

Endothelial Progenitor Cells and a Stromal Cell–derived Factor-1α Analogue Synergistically Improve Survival in Sepsis

1区 · 医学

Article

作者: Halushka, Perry V. ; Cook, James A. ; Zingarelli, Basilia ; Guan, Shuwen ; Goodwin, Andrew J. ; Borg, Keith ; Chang, Eugene ; Fan, Hongkuan

RATIONALEEndothelial progenitor cells (EPCs) have been associated with human sepsis but their role is incompletely understood. Stromal cell-derived factor (SDF)-1α facilitates EPC recruitment and is elevated in murine sepsis models. Previous studies have demonstrated that the SDF-1α analog CTCE-0214 (CTCE) is beneficial in polymicrobial sepsis induced by cecal ligation and puncture (CLP) in mice.OBJECTIVESWe hypothesized that exogenously administered EPCs are also beneficial in CLP sepsis and that CTCE provides synergistic benefit.METHODSMice were subjected to CLP and administered EPCs at varying doses, CTCE, or a combination of the two. Mouse survival, plasma miRNA expression, IL-10 production, and lung vascular leakage were determined. The in vitro effect of CTCE on miRNA expression and EPC function were determined.MEASUREMENTS AND MAIN RESULTSSurvival was improved with EPC therapy at a threshold of 10(6) cells. In coculture studies, EPCs augmented LPS-induced macrophage IL-10 production. In vivo EPC administration in sepsis increased plasma IL-10, suppressed lung vascular leakage, attenuated liver and kidney injury, and augmented miR-126 and -125b expression, which regulate endothelial cell function and/or inflammation. When subthreshold numbers of EPCs were coadministered with CTCE in CLP mice they synergistically improved survival. We demonstrated that CTCE recruits endogenous EPCs in septic mice. In in vitro analysis, CTCE enhanced EPC proliferation, angiogenesis, and prosurvival signaling while inhibiting EPC senescence. These cellular effects were, in part, explained by the effect of CTCE on miR-126, -125b, -34a, and -155 expression in EPCs.CONCLUSIONSEPCs and CTCE represent important potential therapeutic strategies in sepsis.

2013-10-01·Diabetologia1区 · 医学

SDF-1–CXCR4 differentially regulates autoimmune diabetogenic T cell adhesion through ROBO1–SLIT2 interactions in mice

1区 · 医学

Article

作者: John D. Glawe ; Shayne C. Barlow ; Christopher G. Kevil ; Robert McVie ; Eleni M. Mijalis ; Neslihan Gungor ; William C. Davis

AIMS/HYPOTHESISWe had previously reported that stromal cell-derived factor 1 (SDF-1) mediates chemorepulsion of diabetogenic T cell adhesion to islet microvascular endothelium through unknown mechanisms in NOD mice. Here we report that SDF-1-mediated chemorepulsion occurs through slit homologue (SLIT)2-roundabout, axon guidance receptor, homologue 1 (Drosophila) (ROBO1) interactions.METHODSC-X-C receptor (CXCR)4 and ROBO1 protein expression was measured in mouse and human T cells. Parallel plate flow chamber adhesion and detachment studies were performed to examine the molecular importance of ROBO1 and SLIT2 for SDF-1-mediated T cell chemorepulsion. Diabetogenic splenocyte transfer was performed in NOD/LtSz Rag1(-/-) mice to examine the effect of the SDF-1 mimetic CTCE-0214 on adoptive transfer of diabetes.RESULTSCXCR4 and ROBO1 protein expression was elevated in diabetic NOD/ShiLtJ T cells over time and coincided with the onset of hyperglycaemia. CXCR4 and ROBO1 expression was also increased in human type 1 diabetic T cells, with ROBO1 expression maximal at less than 1 year post diagnosis. Cell detachment studies revealed that immunoneutralisation of ROBO1 prevented SDF-1-mediated chemorepulsion of NOD T cell firm adhesion to TNFα-stimulated islet endothelial cells. SDF-1 increased NOD T cell adhesion to recombinant adhesion molecules, a phenomenon that was reversed by recombinant SLIT2. Finally, we found that an SDF-1 peptide mimetic prevented NOD T cell adhesion in vitro and significantly delayed adoptive transfer of autoimmune diabetes in vivo.CONCLUSIONS/INTERPRETATIONThese data reveal a novel molecular pathway, which regulates diabetogenic T cell recruitment and may be useful in modulating autoimmune diabetes.

项与 CTCE-0214 相关的新闻（医药）

2007-10-01

·BioSpace

Chemokine Therapeutics Corp. to Present at BioContact Québec Annual Global Healthcare Conference

VANCOUVER, BRITISH COLUMBIA--(Marketwire - October 01, 2007) - Chemokine Therapeutics Corp. (the "Company") (TSX: CTI)(OTCBB: CHKT), a biotechnology company developing chemokine-based therapies to treat cancer, blood disorders and vascular diseases, today announced that Dr. Bin Huang, Vice President of Corporate Development will be presenting at the BioContact Annual Conference in Quebec City, Canada on Thursday, October 4th, 2007. Dr. Huang will provide an overview of the Company and the Company's two lead drug candidates, CTCE-9908 for the treatment of cancer and CTCE-0214 for neutrophil mobilization both in human clinical trials.

100 项与 CTCE-0214 相关的药物交易

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