title: Impact of a CXCL12/CXCR4 Antagonist in Bleomycin (BLM) Induced Pulmonary Fibrosis and Carbon Tetrachloride (CCl4) Induced Hepatic Fibrosis in Mice.
abstract: Modulation of chemokine CXCL12 and its receptor CXCR4 has been implicated in attenuation of bleomycin (BLM)-induced pulmonary fibrosis and carbon tetrachloride (CCl4)-induced hepatic injury. In pulmonary fibrosis, published reports suggest that collagen production in the injured lung is derived from fibrocytes recruited from the circulation in response to release of pulmonary CXCL12. Conversely, in hepatic fibrosis, resident hepatic stellate cells (HSC), the key cell type in progression of fibrosis, upregulate CXCR4 expression in response to activation. Further, CXCL12 induces HSC proliferation and subsequent production of collagen I. In the current study, we evaluated AMD070, an orally bioavailable inhibitor of CXCL12/CXCR4 in alleviating BLM-induced pulmonary and CCl4-induced hepatic fibrosis in mice. Similar to other CXCR4 antagonists, treatment with AMD070 significantly increased leukocyte mobilization. However, in these two models of fibrosis, AMD070 had a negligible impact on extracellular matrix deposition. Interestingly, our results indicated that CXCL12/CXCR4 signaling has a role in improving mortality associated with BLM induced pulmonary injury, likely through dampening an early inflammatory response and/or vascular leakage. Together, these findings indicate that the CXCL12-CXCR4 signaling axis is not an effective target for reducing fibrosis.
authors.affiliation: The Centre for Drug Research and Development, Vancouver, British Columbia, Canada.
authors.forename: Leola N
authors.initials: LN
authors.lastname: Chow
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Petra
authors.initials: P
authors.lastname: Schreiner
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Betina Y Y
authors.initials: BY
authors.lastname: Ng
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Bernard
authors.initials: B
authors.lastname: Lo
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Hughes
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: R Wilder
authors.initials: RW
authors.lastname: Scott
authors.affiliation: The Centre for Drug Research and Development, Vancouver, British Columbia, Canada.
authors.forename: Vionarica
authors.initials: V
authors.lastname: Gusti
authors.affiliation: The Centre for Drug Research and Development, Vancouver, British Columbia, Canada.
authors.forename: Samantha
authors.initials: S
authors.lastname: Lecour
authors.affiliation: The Centre for Drug Research and Development, Vancouver, British Columbia, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Simonson
authors.affiliation: The Centre for Drug Research and Development, Vancouver, British Columbia, Canada.
authors.forename: Irina
authors.initials: I
authors.lastname: Manisali
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Barta
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Kelly M
authors.initials: KM
authors.lastname: McNagny
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Jason
authors.initials: J
authors.lastname: Crawford
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Murray
authors.initials: M
authors.lastname: Webb
authors.affiliation: The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: T Michael
authors.initials: TM
authors.lastname: Underhill
mesh_terms: D000634:Aminoquinolines; D000818:Animals; D001562:Benzimidazoles; D001761:Bleomycin; D002082:Butylamines; D002251:Carbon Tetrachloride; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006573:Heterocyclic Compounds, 1-Ring / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D008168:Lung / Q000473:pathology; D008214:Lymphocytes / Q000187:drug effects; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000097:blood / Q000150:complications / Q000188:drug therapy; D011658:Pulmonary Fibrosis / Q000097:blood / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000634:Aminoquinolines; D001562:Benzimidazoles; D002082:Butylamines; D054377:Chemokine CXCL12; D006573:Heterocyclic Compounds, 1-Ring; D019718:Receptors, CXCR4; C494414:mavorixafor; D001761:Bleomycin; D002251:Carbon Tetrachloride