Requirement of α4β1 and α5β1 Integrin Expression in Bone-Marrow-Derived Progenitor Cells in Preventing Endotoxin-Induced Lung Vascular Injury and Edema in Mice§

Authors

  • Kishore K. Wary,

    Corresponding author
    1. Department of Pharmacology and Center for Lung and Vascular Biology, The University of Illinois, Chicago, Illinois 60612, USA
    • University of Illinois, 835 South Wolcott Avenue, Room E403, Chicago, Illinois 60612, USA
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    • Author contributions: K.K.W.: conception and design, data collection, analysis, and data interpretation, financial support, manuscript writing, and final approval of manuscript; S.M.V.: data analysis and interpretation; S.G.: animal experiments and data collection; Y.D.Z.: provision of study material; A.B.M.: financial support and manuscript writing.

  • Stephen M. Vogel,

    1. Department of Pharmacology and Center for Lung and Vascular Biology, The University of Illinois, Chicago, Illinois 60612, USA
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  • Sean Garrean,

    1. Department of Pharmacology and Center for Lung and Vascular Biology, The University of Illinois, Chicago, Illinois 60612, USA
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  • Yidan D. Zhao,

    1. Department of Pharmacology and Center for Lung and Vascular Biology, The University of Illinois, Chicago, Illinois 60612, USA
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  • Asrar B. Malik

    1. Department of Pharmacology and Center for Lung and Vascular Biology, The University of Illinois, Chicago, Illinois 60612, USA
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  • First published online in STEM CELLS EXPRESS October 16, 2009; available online without subscription through the open access option.

  • §

    Disclosure of potential conflicts of interest is found at the end of this article.

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Abstract

The goal of this study was to determine the role of integrin-mediated adhesion of bone-marrow-derived progenitor cells (BMPCs) as a requirement for the endothelial barrier protection in a lung injury model. C57BL mice were used as the source for BMPCs, which were characterized as CD34+ and fetal liver kinase-1 (Flk1)+ and also an expression of a repertoire of integrins. We used a mouse model of bacterial lipopolysaccharide (LPS)-induced lung vascular injury and edema formation to test the effects of BMPC integrin expression in preventing endothelial barrier injury. Adhesion of BMPCs to purified extracellular matrix proteins induced focal adhesion kinase (Fak) phosphorylation and formation of branching point structures in a α4 and α5 integrin-dependent manner. BMPCs expressing red fluorescent protein (RFP) were administered via the retro-orbital venous route in mice treated intraperitonially with LPS (7.5 mg/kg body weight). We observed increased retention of RFP-labeled Flk1+ and CD34+ BMPCs for up to 8 weeks in mice injured with LPS. BMPC transplantation increased survival by 50% (at 72–96 hours after LPS) and reduced lung vascular injury and extravascular water content induced by LPS. However, blocking with anti-α4 or anti-α5 integrin antibody or shRNA-mediated silencing of α4 or α5 integrins in donor BMPCs failed to prevent the vascular injury or edema formation and mortality. Thus, α4 and α5 integrin-dependent adhesion of BMPCs in lung tissue plays a critical role in preventing lung vascular injury and increasing survival in a mouse model of LPS-induced acute lung injury. STEM CELLS 2009;27:3112–3120

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