Liver inflammation and fibrosis

Introduction Chronic liver inflammation leads to liver cirrhosis, which is the 12th leading cause of death in the US (1), accounting for 32,000 deaths in the US and more than 1 million deaths each year worldwide (2). Chronic pathologic processes include viral infection, alcoholic liver disease, nonalcoholic steatohepatitis (NASH), and autoimmune diseases. Depending on the type of underlying liver injury, several mechanisms exist to trigger immune reactions. Chronic immune reactions lead to liver fibrosis. Understanding the mechanism of inflammation and fibrosis is critically important to developing treatments for chronic liver diseases. Hepatic steatosis is a common consequence of metabolic or toxic stress. This steatosis may progress to hepatic injury in response in alcohol (alcoholic steatohepatitis [ASH]), toxins such as vinyl chloride (toxicant-associated steatohepatitis), chemotherapy (chemotherapy-associated steatohepatitis), or metabolic syndrome with insulin resistance (NASH), which is the most common liver disease in the US (3, 4). Injury changes hepatocyte gene expression, resulting in increased expression of TGF-β, IL-1A, hedgehog ligands, CXCL10, and mesenchymal genes such as twist and snail. The injured steatotic hepatocyte induces inflammation and fibrosis. Even under physiologic conditions the liver is constantly exposed to exogenous proteins derived from foods, chemicals, drugs, and microbiota in the gut. Immunologically, the liver capillary system is lined with resident macrophages (Kupffer cells) and liver DCs. In pathologic conditions, bone marrow–derived cells, such as infiltrating macrophages, migrate to the liver and work in collaboration with the resident cells. Because of the difficulty in cellular isolation techniques, the inflammatory responses in the liver are not fully understood. In this Review we discuss initiation of inflammation in the liver, inflammatory cells, and their crosstalk with myofibroblasts.