Treatment of liver disease, caused by hepatotoxins, viral infections, alcohol ingestion, or autoimmune conditions, remains challenging and costly. The liver has a powerful capacity to repair and regenerate, thus a thorough understanding of this tightly orchestrated process will undoubtedly improve clinical means of restoring liver function after injury. Using a murine model of acute liver injury caused by overdose of acetaminophen (APAP), our studies demonstrated that the combined absence of liver resident macrophages (Kupffer cells, KCs), and infiltrating macrophages (IMs) resulted in a marked delay in liver repair, even though the initiation and extent of peak liver injury was not impacted. This delay was not due to impaired hepatocyte proliferation but rather prolonged vascular leakage, which is caused by APAP-induced liver sinusoidal endothelial cell (LSEC) injury. We also found that KCs and IMs express an array of angiogenic factors and induce LSEC proliferation and migration. Our mechanistic studies suggest that hypoxia-inducible factor (HIF) may be involved in regulating the angiogenic effect of hepatic macrophages (Macs), as we found that APAP challenge resulted in hypoxia and stabilization of HIF in the liver and hepatic Macs. Together, these data indicate an important role for hepatic Macs in liver blood vessel repair, thereby contributing to tissue recovery from acute injury.
Keywords: ADM; ADORA2A; AILI; ANGPTL; APAP; Acetaminophen; Angiogenesis; C-X-C chemokine receptor type 4; CA-9; CXCR4; EPO; Glut-1; HIF; IMs; KCs; Kupffer cells; LSECs; MCP-1; MMP; Macs; Microvasculature; NPCs; PAI-1; STAT4; TAMs; VEGF; acetaminophen; acetaminophen (APAP)-induced liver injury; adenosine receptor A2a; adrenomedullin; angiopoietin-like; carbonic anhydrase-9; erythropoietin; glucose transporter-1; hypoxia-inducible factor; i.p.; i.v.; infiltrating macrophages; intraperitoneal; intravenous; lipo/cld; liposome/clodronate; liver sinusoidal endothelial cells; macrophage chemotactic protein-1; macrophages; matrix metalloproteinase; nonparenchymal cells; plasminogen activator inhibitor-1; signal transducer and activator of transcription 4; tumor-associated Macs; vascular endothelial growth factor.
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