CXCL11 attenuates bleomycin-induced pulmonary fibrosis via inhibition of vascular remodeling.
Aberrant vascular remodeling is a central hallmark for the development and progression of idiopathic pulmonary fibrosis. The mechanisms underlying the pathophysiologic alterations, however, are poorly understood. A recent phase II trial of interferon gamma-1b has demonstrated a trend toward a decrease in profibrotic and proangiogenic biologic markers, and upregulation of lung CXCL11 mRNA and bronchoalveolar lavage fluid and plasma protein levels of CXCL11. We hypothesized that net aberrant vascular remodeling seen during the pathogenesis of fibroplasia and deposition of extracellular matrix during bleomycin-induced pulmonary fibrosis can be attenuated by treatment with the angiostatic ELR(-) CXC chemokine, CXCL11. In a preclinical model, systemic administration of CXCL11 reduced pulmonary collagen deposition, procollagen gene expression, and histopathologic fibroplasia and extracellular matrix deposition in the lung of bleomycin-treated mice. CXCL11 treatment significantly reduced bleomycin-induced pulmonary fibrosis without altering specific lung leukocyte populations. CXCR3 is not expressed on fibroblasts and CXCL11 had no direct functional effect on pulmonary fibroblasts. The angiogenic activity in the lung was significantly decreased, however, and CXCL11 treatment reduced the total number of endothelial cells in the lung following bleomycin exposure. The results suggest that CXCL11 inhibits pulmonary fibrosis by altering aberrant vascular remodeling.
Burdick
Marie D
MD
Division of Pulmonary and Critical Care Medicine, Department of Medicine, UCLA School of Medicine, Los Angeles, CA, USA.
Murray
Lynne A
LA
Keane
Michael P
MP
Xue
Ying Ying
YY
Zisman
David A
DA
Belperio
John A
JA
Strieter
Robert M
RM
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D001761:Bleomycin / Q000009:adverse effects*; D002452:Cell Count; D054371:Chemokine CXCL11; D019743:Chemokines, CXC / Q000627:therapeutic use*; D003094:Collagen / Q000187:drug effects; D004195:Disease Models, Animal; D018450:Disease Progression; D042783:Endothelial Cells / Q000187:drug effects; D004730:Endothelium, Vascular / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects; D005347:Fibroblasts / Q000187:drug effects; D007958:Leukocyte Count; D007962:Leukocytes / Q000187:drug effects; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D051379:Mice; D009389:Neovascularization, Pathologic / Q000139:chemically induced / Q000188:drug therapy*; D011347:Procollagen / Q000187:drug effects; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000188:drug therapy*
D020533:Angiogenesis Inhibitors; D000903:Antibiotics, Antineoplastic; D054371:Chemokine CXCL11; D019743:Chemokines, CXC; C515203:Cxcl11 protein, mouse; D011347:Procollagen; D001761:Bleomycin; D003094:Collagen