Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis.
Fibrotic interstitial lung diseases are characterized by progressive decline in lung function and premature death from respiratory failure. Fibrocytes are circulating bone marrow-derived progenitor cells that traffic to the lungs and contribute to fibrosis and may represent novel therapeutic targets in these diseases. We have previously found the recruitment of fibrocytes to the lung to be dependent on the chemokine ligand CXCL12. Given that the expression of the CXCL12 receptor, CXCR4, can be modulated pharmacologically in other cell types, we tested the hypotheses that the regulation of CXCR4 expression on fibrocytes mediates their influx to the lung in the context of pulmonary fibrosis and that pharmacologic inhibition of this process results in attenuated disease severity. CXCR4 was the predominant chemokine receptor on human fibrocytes, and its expression on fibrocytes was enhanced by hypoxia and by growth factors including platelet-derived growth factor. Both hypoxia-induced and growth factor-induced CXCR4 expressions were attenuated by specific inhibition of PI3-kinase and mTOR. Finally, in the mouse model of bleomycin-induced pulmonary fibrosis, treatment with the mTOR inhibitor rapamycin resulted in reduced numbers of CXCR4-expressing fibrocytes in the peripheral blood and lung as well as reduced lung collagen deposition. Taken together, these experiments support the notion that pharmacologic inhibition of the CXCR4/CXCL12 biological axis is achievable in human fibrocytes and reduces the magnitude of pulmonary fibrosis in an animal model. This approach may hold promise in human fibrotic lung diseases.
Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of Virginia, Charlottesville, VA 22908, United States.
Borna
B
Mehrad
Marie D
MD
Burdick
Robert M
RM
Strieter
D000818:Animals; D001761:Bleomycin; D015687:Cell Hypoxia / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000473:pathology; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D011658:Pulmonary Fibrosis / Q000378:metabolism* / Q000628:therapy*; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D015854:Up-Regulation / Q000187:drug effects
D001761:Bleomycin; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D036341:Intercellular Signaling Peptides and Proteins; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D019718:Receptors, CXCR4; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C527276:CXCR4 protein, human; C514936:CXCR4 protein, mouse; C497442:HIF1A protein, human; C546842:MTOR protein, human; C546843:mTOR protein, mouse