This Article Full Text Full Text (PDF) All Versions of this Article: 2004-0175OCv1 31/4/395    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tager, A. M. Articles by Luster, A. D. Search for Related Content PubMed PubMed Citation Articles by Tager, A. M. Articles by Luster, A. D.

Inhibition of Pulmonary Fibrosis by the Chemokine IP-10/CXCL10

Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy, and Immunology; Pulmonary and Critical Care Unit; and Immunopathology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; and Division of Allergy, Pulmonary, and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee

Address correspondence to: Andrew D. Luster, M.D., Ph.D., Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Building 149-8301, 13th Street, Charlestown, MA 02129. E-mail: luster{at}helix.mgh.harvard.edu

Pulmonary fibrosis is an enigmatic and devastating disease with few treatment options, now thought to result from abnormal wound healing in the lung in response to injury. We have previously noted a role for the chemokine interferon –inducible protein of 10 kD (IP-10)/CXC chemokine ligand 10 in the regulation of cutaneous wound healing, and consequently investigated whether IP-10 regulates pulmonary fibrosis. We found that IP-10 is highly expressed in a mouse model of pulmonary fibrosis induced by bleomycin. IP-10–deficient mice exhibited increased pulmonary fibrosis after administration of bleomycin, suggesting that IP-10 limits the development of fibrosis in this model. Substantial fibroblast chemoattractant and proliferative activities were generated in the lung after bleomycin exposure. IP-10 significantly inhibited fibroblast responses to the chemotactic, but not the proliferative activity generated, suggesting that IP-10 may attenuate fibroblast accumulation in bleomycin-induced pulmonary fibrosis by limiting fibroblast migration. Consistent with this inhibitory activity of IP-10 on fibroblast migration, fibroblast accumulation in the lung after bleomycin exposure was dramatically increased in IP-10–deficient mice compared with wild-type mice. Conversely, transgenic mice overexpressing IP-10 were protected from mortality after bleomycin exposure, and demonstrated decreased fibroblast accumulation in the lung after challenge compared with wild-type mice. Our findings suggest that interruption of fibroblast recruitment may represent a novel therapeutic strategy for pulmonary fibrosis, which could have applicability to a wide range of fibrotic illnesses.

Abbreviations: bronchoalveolar lavage fluid, BALF • basic fibroblast growth factor, bFGF • CXC chemokine ligand, CXCL • CXC chemokine receptor, CXCR • Dulbecco's modified Eagle's medium, DMEM • ethylenediaminetetraacetate, EDTA • epidermal growth factor, EGF • enzyme-linked immunosorbent assay, ELISA • fetal bovine serum, FBS • fibroblast-specific protein, FSP • glyceraldehyde-3-phosphate dehydrogenase, GAPDH • glycosaminoglycan, GAG • interleukin, IL • interferon –inducible protein of 10 kD, IP-10 • interferon-inducible T cell alpha chemoattractant, I-TAC • knockout, KO • monokine induced by interferon , Mig • natural killer, NK • phosphate-buffered saline, PBS • polymerase chain reaction, PCR • phycoerythrin, PE • T helper, Th • von Willebrand Factor, vWF • wild-type, WT

This article has been cited by other articles:

				K. A. Brant and J. P. Fabisiak Nickel Alterations of TLR2-Dependent Chemokine Profiles in Lung Fibroblasts Are Mediated by COX-2 Am. J. Respir. Cell Mol. Biol., May 1, 2008; 38(5): 591 - 599. [Abstract] [Full Text] [PDF]

				A. U. Wells and C. M. Hogaboam Update in Diffuse Parenchymal Lung Disease 2006 Am. J. Respir. Crit. Care Med., April 1, 2007; 175(7): 655 - 660. [Full Text] [PDF]

				I. V. Yang, L. H. Burch, M. P. Steele, J. D. Savov, J. W. Hollingsworth, E. McElvania-Tekippe, K. G. Berman, M. C. Speer, T. A. Sporn, K. K. Brown, et al. Gene Expression Profiling of Familial and Sporadic Interstitial Pneumonia Am. J. Respir. Crit. Care Med., January 1, 2007; 175(1): 45 - 54. [Abstract] [Full Text] [PDF]

				P. Pignatti, G. Brunetti, D. Moretto, M.-R. Yacoub, M. Fiori, B. Balbi, A. Balestrino, G. Cervio, S. Nava, and G. Moscato Role of the Chemokine Receptors CXCR3 and CCR4 in Human Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., February 1, 2006; 173(3): 310 - 317. [Abstract] [Full Text] [PDF]

				C. Agostini and C. Gurrieri Chemokine/Cytokine cocktail in idiopathic pulmonary fibrosis. Proceedings of the ATS, January 1, 2006; 3(4): 357 - 363. [Abstract] [Full Text] [PDF]

				K. Chen, Y. Wei, A. Alter, G. C. Sharp, and H. Braley-Mullen Chemokine expression during development of fibrosis versus resolution in a murine model of granulomatous experimental autoimmune thyroiditis J. Leukoc. Biol., September 1, 2005; 78(3): 716 - 724. [Abstract] [Full Text] [PDF]

				T. Murakawa, M. M. Kerklo, M. R. Zamora, Y. Wei, R. G. Gill, P. M. Henson, F. L. Grover, and M. R. Nicolls Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis J. Immunol., April 1, 2005; 174(7): 3869 - 3879. [Abstract] [Full Text] [PDF]

				M. D. Burdick, L. A. Murray, M. P. Keane, Y. Y. Xue, D. A. Zisman, J. A. Belperio, and R. M. Strieter CXCL11 Attenuates Bleomycin-induced Pulmonary Fibrosis via Inhibition of Vascular Remodeling Am. J. Respir. Crit. Care Med., February 1, 2005; 171(3): 261 - 268. [Abstract] [Full Text] [PDF]