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.

Insulin-like growth factor binding protein-4 exerts antifibrotic activity by reducing levels of connective tissue growth factor and the C-X-C chemokine receptor 4

“…CXCR4 is a G-protein coupled receptor that consists of seven transmembrane proteins and is widely expressed in various tissues. 43 Our results demonstrate increased CXCR4 expression in SSc lung fibroblasts paralleling reduced levels of IGFBP-4. SDF-1, acting via CXCR4, recruits circulating monocytes, fibrocytes, and other cells to the injured lung and their transformation into myofibroblasts, the effector cells in fibrosis.…”

“…37,38,40 Although one group did not detect a decrease in extracellular matrix deposition in injured lung, animal mortality was reduced as a result of a decreased inflammatory response. 43 Our results demonstrate increased CXCR4 expression in SSc lung fibroblasts paralleling reduced levels of IGFBP-4. The increased CXCR4 levels are consistent with the findings from other groups where CXCR4 expression was measured in lung tissues and peripheral blood monocytes.…”

RETRACTED ARTICLE: Chemokine receptor 7 overexpression promotes mesenchymal stem cell migration and proliferation via secreting Chemokine ligand 12

“…In previous studies, the expression of CXCL12 increased significantly in injured and hypoxic tissues 10 , 35 , 36 . Thus, additional CXCL12 was added to the lower chambers of transwell assays to simulate the microenvironment of injured and hypoxic tissues.…”

Combined delivery of sorafenib and a MEK inhibitor using CXCR4-targeted nanoparticles reduces hepatic fibrosis and prevents tumor development

“…The PLGA NPs that had slow-release properties significantly extended the blood circulation of the cargo and enhanced drug accumulation in the fibrotic livers 39 . We further modified the PLGA NPs with peptides targeting CXCR4 to achieve ligand-mediated targeting to HSCs wherein CXCR4 expression was upregulated in response to activation 40 . Sorafenib and MEK inhibitors co-delivered by the CXCR4-targeted NPs prevented MAPK activation, suppressed hepatic fibrosis progression and attenuated angiogenesis in the fibrotic livers of CCl 4 -treated mice with no apparent toxicity.…”