Inhibition of pulmonary fibrosis by the chemokine IP-10/CXCL10.
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 gamma-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.
Tager
Andrew M
AM
Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Building 149-8301, 13th Street, Charlestown, MA 02129, USA.
Kradin
Richard L
RL
LaCamera
Peter
P
Bercury
Scott D
SD
Campanella
Gabriele S V
GS
Leary
Carol P
CP
Polosukhin
Vasiliy
V
Zhao
Long-Hai
LH
Sakamoto
Hideo
H
Blackwell
Timothy S
TS
Luster
Andrew D
AD
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D001761:Bleomycin / Q000633:toxicity; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000235:genetics / Q000502:physiology*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology*; D007371:Interferon-gamma / Q000378:metabolism; D007694:Killer Cells, Natural / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000276:immunology / Q000517:prevention & control*; D015996:Survival Rate; D013601:T-Lymphocytes / Q000378:metabolism; D014841:von Willebrand Factor / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D014841:von Willebrand Factor; D001761:Bleomycin; D007371:Interferon-gamma