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Adenovirally Mediated Expression of Urokinase Receptor Binding Site on Integrin α-Chain Blocks Adhesion and Migration of Human Lung Fibroblasts*

Sha Zhu, PhD; Candece L. Gladson, MD; Jerry Stewart; Kimberly E. White; Harold A. Chapman, Jr., MD; Mitchell A. Olman, MA, MD
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*From the Departments of Medicine (Dr. Zhu and Ms. White) and Pathology (Drs. Gladson, Olman, and Mr. Stewart), Division of Pulmonary and Critical Care Medicine, University of Alabama, Birmingham AL; and the Cardiovascular Research Institute (Dr. Chapman), University of California at San Francisco, San Francisco, CA.

Correspondence to: Mitchell A. Olman, MD, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Alabama at Birmingham Medical Center, 1900 University Blvd, 215 THT, Birmingham, AL 35294; e-mail: Olman@uab.edu.



Chest. 2002;121(3_suppl):34S-35S. doi:10.1378/chest.121.3_suppl.34S
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Attachment and migration of fibroblasts to the vitronectin- and fibronectin-rich alveolar matrices are critical processes in wound repair after acute lung injury. This study was undertaken to determine the mechanism by which human lung fibroblasts attach and migrate toward provisional alveolar matrix proteins, and to develop mechanism-based, novel therapeutic agents designed to specifically inhibit these functions. We have previously demonstrated urokinase plasminogenactivator receptor (u-PAR) and a functional fibrinolytic system on these cells. Analysis of surface integrins reveals expression of the vitronectin receptors αvβ3, αvβ5, αvβ1, and α8β1. Fibroblast attachment to vitronectin was inhibited by 50 μg/mL of anti–u-PAR IgG (70%), monoclonal antibody (mAb) anti-β1 integrin (80%), and mAb anti-αvβ5 integrin (30%), but not by mAb to αvβ3, α3, and α5 integrins in the presence of 1 mM Ca++. These data suggest that u-PAR–integrin interactions play an important role in fibroblast attachment to provisional alveolar matrix proteins. Furthermore, a peptide homologous to the u-PAR binding site on integrin α-chains also blocked cell attachment to vitronectin in a concentration-dependent manner (70% at 100 μM), while the control scrambled peptide had no effect. These data suggest that u-PAR interacts with αvβ1 or α8β1 in mediating fibroblast attachment to vitronectin. A replication-deficient adenovirus encoding for the u-PAR binding region of the integrin α-chain was generated, and adenoviral infection of human lung fibroblasts was optimized. Adenovirally infected fibroblasts (multiplicity of infection = 500, 48 h) had reduced migration toward vitronectin (50%) and fibronectin (30%) in a haptotactic migration assay (6 h, 1 mM Ca++), whereas the migration of cells infected with a control virus encoding the scrambled peptide was similar to that seen in uninfected cells. Similarly, adenovirally infected fibroblasts (multiplicity of infection = 500, 48 h) had reduced attachment toward vitronectin (50%), fibronectin (30%), and collagen (30%) compared to control and uninfected cells. Taken together, these data suggest that u-PAR–integrin interaction(s) modulate fibroblast attachment and migration toward provisional alveolar matrix proteins. Integrin α-chain peptide-encoding adenovirus may provide a novel antiadhesive therapeutic approach for abrogating the fibroproliferative response after lung injury.

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