title: Neutralization of the CXC chemokine, macrophage inflammatory protein-2, attenuates bleomycin-induced pulmonary fibrosis.
abstract: Few studies have addressed the importance of vascular remodeling in the lung during the development of bleomycin-induced pulmonary fibrosis. 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 bleomycin-induced pulmonary fibrosis are dependent in part upon an overexpression of the angiogenic CXC chemokine, macrophage inflammatory protein-2 (MIP-2). To test this hypothesis, we measured MIP-2 by specific ELISA in whole lung homogenates in either bleomycin-treated or control CBA/J 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 significant increase in the presence of MIP-2 that was correlated to a greater angiogenic response and total lung hydroxyproline content. Neutralizing anti-MIP-2 Abs inhibited the angiogenic activity of day 16 bleomycin-treated lung specimens using an in vivo angiogenesis bioassay. Furthermore, when MIP-2 was depleted in vivo by passive immunization, bleomycin-induced pulmonary fibrosis was significantly reduced without a change in the presence of pulmonary neutrophils, fibroblast proliferation, or collagen gene expression. This was also paralleled by a reduction in angiogenesis. These results demonstrate that the angiogenic CXC chemokine, MIP-2, is an important factor that regulates angiogenesis/fibrosis in pulmonary fibrosis.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan Medical School, Ann Arbor 48109, USA.
authors.forename: M P
authors.initials: MP
authors.lastname: Keane
authors.forename: J A
authors.initials: JA
authors.lastname: Belperio
authors.forename: T A
authors.initials: TA
authors.lastname: Moore
authors.forename: B B
authors.initials: BB
authors.lastname: Moore
authors.forename: D A
authors.initials: DA
authors.lastname: Arenberg
authors.forename: R E
authors.initials: RE
authors.lastname: Smith
authors.forename: M D
authors.initials: MD
authors.lastname: Burdick
authors.forename: S L
authors.initials: SL
authors.lastname: Kunkel
authors.forename: R M
authors.initials: RM
authors.lastname: Strieter
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity*; D002454:Cell Differentiation / Q000276:immunology; D002465:Cell Movement / Q000276:immunology; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000276:immunology* / Q000502:physiology; D003094:Collagen / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000473:pathology; D005786:Gene Expression Regulation / Q000276:immunology; D007106:Immune Sera / Q000008:administration & dosage; D007116:Immunization, Passive; D007150:Immunohistochemistry; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D015846:Monokines / Q000096:biosynthesis / Q000276:immunology* / Q000502:physiology; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control; D009504:Neutrophils / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000139:chemically induced* / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D051381:Rats; D020318:Rats, Long-Evans
chemical_list: D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D007106:Immune Sera; D015846:Monokines; D001761:Bleomycin; D003094:Collagen