An investigation of the cellular mechanisms regulated by CXCR7 during hepatic and pulmonary fibrosis.

Fibrosis of the lungs and liver, characterised by excessive extra-cellular matrix (ECM) deposition and scarring following injury, has a significant negative impact on health worldwide. The incidence of these conditions is increasing, however their development and cause are poorly understood. Immune signaling molecules known as chemokines and their receptors have been implicated in fibrogenesis. Our laboratory previously found the chemokine receptor CXCR7 to be implicated in lung and liver fibrosis, as blocking CXCR7 with specific antibodies or knocking CXCR7 out genetically reduced total collagen deposition and expression of other markers of fibrosis significantly in 2 models of lung fibrosis and 1 model of liver fibrosis. In the lung CXCR7 was detected in bronchial epithelial cells.Aims: In this study we sought to validate CXCR7 involvement in a second model of hepatic fibrosis and to define the cell types expressing CXCR7 in normal and fibrotic livers. Furthermore, we investigated the mechanisms regulated by CXCR7 in vitro.Results: During liver fibrosis Cxcr7 mRNA was upregulated in all models in parallel to several common markers of fibrosis. CXCR7 mRNA was also found to be upregulated in human cirrhotic liver. In a CCl4-induced liver fibrosis model, Cxcr7 KO prevented upregulation of several of these fibrosis markers.In the liver Cxcr7 was found to be expressed in the membrane of hepatocytes with a strong signal on the bile canaliculi. Cxcr7 could not be detected on endothelial cells or hepatic stellate cells, the fibroblasts of the liver.Treatment of transformed human bronchial epithelial Beas-2B cells in vitro with profibrogenic factor TGF-β resulted in upregulation of the mRNA of Cxcr7 and markers of fibrosis as expected, however blocking Cxcr7 or stimulating Cxcr7 with ligand did not have any effect.From this it can be concluded that CXCR7 is expressed in cells of epithelial origin in the liver (hepatocytes) and is upregulated during liver fibrosis. It was shown to have profibrotic effect in an additional model (CCl4-induced) of liver fibrosis. CXCL7 levels paralleled fibrotic marker levels both in vivo and in vitro. This study shows CXCR7 is a critical component of profibrogenic signaling and future work should focus on these cell types that express it to explore mechanisms of fibrotic activity by CXCR7. This will lead to a better understanding of lung and liver fibrogenesis and perhaps a potential therapeutic to block the receptor in human patients