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.
Highlights
Hepatic fibrosisHepatic fibrosis is a pathological wound healing response to liver damage that is characterized by excess production and deposition of extracellular matrix (ECM) components [1,2,3]
Our results suggest that AMD070 was able to increase survival in BLM-induced pulmonary fibrosis (PF) but surprisingly, had no effect on lung fibrosis
Prior to the efficacy study of AMD070 administered by PO in the BLM-induced lung fibrosis model, we wished to confirm that AMD070 given by this route would accumulate in the lungs and in addition, had the anticipated effects on white blood cell (WBC) counts
Summary
Hepatic fibrosis is a pathological wound healing response to liver damage that is characterized by excess production and deposition of extracellular matrix (ECM) components [1,2,3]. Insults that can trigger a fibrotic response include viral infection, alcohol or drug toxicity, metabolic diseases and a variety of factors that induce an inflammation response in the liver [1, 4, 5]. AMD070 in Murine Models of Lung and Liver Fibrosis PLOS ONE | DOI:10.1371/journal.pone.0151765 March 21, 2016
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