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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

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