AJP - Lung Add DOIs to your references at manuscript stage!
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Lung Cell Mol Physiol 297: L97-L108, 2009. First published May 1, 2009; doi:10.1152/ajplung.90283.2008
1040-0605/09 $8.00
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow All Versions of this Article:
297/1/L97    most recent
90283.2008v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Google Scholar
Right arrow Articles by Zhu, S.
Right arrow Articles by Olman, M. A.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Zhu, S.
Right arrow Articles by Olman, M. A.

Urokinase receptor mediates lung fibroblast attachment and migration toward provisional matrix proteins through interaction with multiple integrins

Sha Zhu,1 Candece L. Gladson,2,5 Kimberly E. White,1 Qiang Ding,1 Jerry Stewart, Jr.,2 Tong H. Jin,1,5 Harold A. Chapman, Jr.,3 and Mitchell A. Olman1,2,4

Departments of 1Medicine and 2Pathology, University of Alabama at Birmingham, Birmingham, Alabama; 3Cardiovascular Research Institute, University of California at San Francisco, San Francisco, California; and Departments of 4Pathobiology and 5Cancer Biology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio

Submitted 21 April 2008 ; accepted in final form 27 April 2009

Fibroblasts from patients with pulmonary fibrosis express higher levels of the receptor for urokinase, and the extent of fibrosis in some animal models exhibits a dependence on the urokinase receptor. Recent observations have identified the urokinase receptor as a trans-interacting receptor with consequences on signaling and cell responses that vary depending on its interacting partner, the relative levels of expression, and the state of cellular transformation. We undertook this study to define the urokinase-type plasminogen activator cellular receptor (u-PAR)-integrin interactions and to determine the functional consequences of such interactions on normal human lung fibroblast attachment and migration. u-PAR colocalizes in lammelipodia/filopodia with relevant integrins that mediate fibroblast attachment and spreading on the provisional matrix proteins vitronectin, fibronectin, and collagens. Inhibitory antibody studies have revealed that human lung fibroblasts utilize {alpha}vβ5 to attach to vitronectin, predominantly {alpha}5β1 (and {alpha}vβ3) to attach to fibronectin, and {alpha}1β1, {alpha}2β1, and {alpha}3β1 to attach to collagen. Blocking studies with {alpha}-integrin subunit decoy peptides and u-PAR neutralizing antibodies indicate that u-PAR modulates the integrin-mediated attachment to purified provisional matrix proteins, to anti-integrin antibodies, or to fibroproliferative lesions from fibrotic lungs. Furthermore, these decoy peptides blunt fibroblast spreading and migration. We show that u-PAR can interact with multiple {alpha}-integrins but with a preference for {alpha}3. Taken together, these data demonstrate that u-PAR may interact with multiple integrins in normal human lung fibroblasts thereby promoting attachment, spreading, and migration. Modulation of fibroblast invasion would be expected to lead to amelioration of fibroproliferative diseases of the lung.

pulmonary; fibrosis; plasmin


Address for reprint requests and other correspondence: M. A. Olman, Staff, Dept. of Pathobiology, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave. NC-22, Cleveland, OH 44195 (e-mail: Olmanm{at}ccf.org)






HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Visit Other APS Journals Online
Copyright © 2009 by the American Physiological Society.