IFN-gamma-inducible protein-10 attenuates bleomycin-induced pulmonary fibrosis via inhibition of angiogenesis.
Few studies have addressed the importance of vascular remodeling in the lung during the development of bleomycin-induced pulmonary fibrosis (BPF). For fibroplasia and deposition of extracellular matrix to occur, there must be a geometric increase in neovascularization. We hypothesized that net angiogenesis during the pathogenesis of fibroplasia and deposition of extracellular matrix during BPF are dependent in part on a relative deficiency of the angiostatic CXC chemokine, IFN-gamma-inducible protein-10 (IP-10). To test this hypothesis, we measured IP-10 by specific ELISA in whole lung homogenates in either bleomycin-treated or control mice and correlated these levels with lung hydroxyproline. We found that lung tissue from mice treated with bleomycin, compared with that from saline-treated controls, demonstrated a decrease in the presence of IP-10 that was correlated to a greater angiogenic response and total lung hydroxyproline content. Systemic administration of IP-10 significantly reduced BPF without any alteration in lung lymphocyte or NK cell populations. This was also paralleled by a reduction in angiogenesis. Furthermore, IP-10 had no direct effect on isolated pulmonary fibroblasts. These results demonstrate that the angiostatic CXC chemokine, IP-10, inhibits fibroplasia and deposition of extracellular matrix by regulating angiogenesis.
Keane
M P
MP
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor 48109, USA.
Belperio
J A
JA
Arenberg
D A
DA
Burdick
M D
MD
Xu
Z J
ZJ
Xue
Y Y
YY
Strieter
R M
RM
D000276:Adjuvants, Immunologic / Q000502:physiology*; D000818:Animals; D001681:Biological Assay; D001761:Bleomycin / Q000633:toxicity*; D002455:Cell Division / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D016510:Corneal Neovascularization / Q000276:immunology / Q000517:prevention & control; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000276:immunology; D007371:Interferon-gamma / Q000502:physiology*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D016131:Lymphocyte Subsets / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000517:prevention & control*; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D051381:Rats; D020318:Rats, Long-Evans
D000276:Adjuvants, Immunologic; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; D001761:Bleomycin; D007371:Interferon-gamma