Published ahead of print on June 17, 2004, doi:10.1165/rcmb.2004-0175OC
Am. J. Respir. Cell Mol. Biol., Volume 31, Number 4, October 2004, 395-404
A more recent version of this article appeared on October 1, 2004
Submitted on June 1, 2004
Revised on June 16, 2004
Inhibition of Pulmonary Fibrosis by the Chemokine IP-10/CXCL10
Andrew M Tager1, Richard L Kradin2, Peter LaCamera1, Scott D Bercury3, Gabriele S.V. Campanella3, Carol P Leary3, Vasiliy Polosukhin4, Long-Hai Zhao5, Hideo Sakamoto5, Timothy S Blackwell4, and Andrew D Luster3*
1 Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Charlestown, Massachusetts, USA; Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts, USA,
2 Pulmonary and Critical Care Unit, Massachusetts General Hospital, Boston, Massachusetts, USA; Immunopathology Unit, Massachusetts General Hospital, Boston, Massachusetts, USA,
3 Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Charlestown, Massachusetts, USA,
4 Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA,
5 Immunopathology Unit, Massachusetts General Hospital, Boston, Massachusetts, USA
* To whom correspondence should be addressed. E-mail: aluster{at}partners.org.
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 kDa (IP-10)/CXC chemokine ligand (CXCL) 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 following bleomycin, suggesting that IP-10 limits the development of fibrosis in this model. Substantial fibroblast chemoattractant and proliferative activities were generated in the lung following 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 following bleomycin was dramatically increased in IP-10-deficient mice compared to wild-type mice. Conversely, transgenic mice over-expressing IP-10 were protected from mortality following bleomycin, and demonstrated decreased fibroblast accumulation in the lung after challenge compared to 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.
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