Mediators of Hepatic Inflammation

When microbes and other inflammatory stimuli first enter the hepatic circulation, they activate sinusoidal endothelial cells and Kupffer cells. These cells then produce a cocktail of proinflammatory mediators such as prostanoids, nitric oxide, cytokines, chemokines, many growth factors, and reactive oxygen species. With the increased expression of these inflammatory mediators comes (1) the recruitment of leukocytes into the inflamed area, (2) the killing of the invading microbes, and in some cases (3) damage to liver parenchymal cells. For more elaborate discussions on the mediators of hepatic inflammation, we recommend the following reviews: Ref. [4-7].

Vasocontriction and Vasodilation

Alterations to blood flow within the liver have a significant impact on liver function. Several vasoactive substances can affect constriction and relaxation of hepatic stellate cells. These mediators have been shown to come from stellate cells themselves (endothelin-1, NO) as well as hepato-cytes (carbon monoxide, leukotrienes), endothelial cells (endothelin, nitric oxide, prostaglandins), and Kupffer cells (prostaglandins, NO). Notably, during the early phase of sepsis both nitric oxide (NO) and carbon monoxide (CO) act as antagonists of vasoconstrictors (e.g., endothelin-1) by mediating relaxation of sinusoidal vessels such that there is an increase in vasodilation. In acute and chronic hepatic inflammation, dysregulation of the vasoactive substances can result in a circulatory collapse within the liver.

Reactive Oxygen Species

Reactive oxygen species (ROS) are important cytotoxic and signaling mediators in the pathophysiology of inflammatory liver diseases. They can be generated by resident and nonresident liver cells following stimulation. ROS are essential for host-defense functions of phagocytes. In addition, ROS have been shown to indirectly affect vasoconstriction and liver regeneration. Although ROS are able to induce cell damage, they also modulate signal transduction pathways by regulating transcription factors such as NF-kB. By regulating NF-kB, ROS can indirectly affect the pathophysiology of the liver by (1) directly inducing and/or regulating apoptotic and necrotic cell death and (2) modulating the expression of inflammatory mediators and adhesion molecules.


Prostaglandins and leukotrienes are ubiquitous mediators of liver function and disease. In the inflamed liver, Kupffer cells produce prostaglandins to modulate hepatic glucose metabolism. Upregulation of glucose correlates with the increasing demand for energetic fuel by the inflammatory cells such as leukocytes, sinusoidal endothelial cells, and Kupffer cells. Studies have also demonstrated a protective role of PGE2 in viral hepatitis as it abrogates the induction of TNFa, attenuating the expression of antigens on hepato-cytes, and may inhibit viral replication. By contrast, in cirrhosis and fulminant hepatic failure a dysregulation of prostaglandin metabolism has been noted. Leukotrienes (e.g., LTB4) have vasoconstrictive and metabolic effects in the liver. These mediators have been shown to cause liver injury in ischemia-reperfusion and endotoxemia.


Experimental data have demonstrated a critical role for proinflammatory cytokines (e.g., TNFa, IL-1, and IFNg in the development of liver injury. Although TNFa is required for normal hepatocyte proliferation during liver regeneration, it is also involved in inflammation. TNFa is known to induce the transcription factor nuclear factor-kappaB (NF-kB) which regulates many proinflammatory mediators (e.g., TNFa and IL-1). Overexpression of TNFa (from Kupffer cells or infiltrating neutrophils) has been shown to correlate with hepatotoxicity in endotoxemia, alcoholic liver disease, and viral hepatitis. Another cytokine noted for its involvement in liver injury is IFNg. In alcoholic hepatitis, overexpression of IFNg mediates liver injury. By contrast, in viral hepatitis it is a lack of functioning IFNg that permits the liver damage.


The recruitment of inflammatory cells to the liver is a critical step to the development of liver disease. Chemo-kines have emerged as one of the most important regulators of leukocyte trafficking and activation. In the noninflamed liver resident cells express and secrete low levels of CCL5 (RANTES), CCL2 (MCP-1), CCL3 (MIP-1a), CCL4 (MIP-lb), and IL-8. These chemokines have been detected on the vascular endothelium in portal tracts as well as the sinusoids. Interestingly, inflammation-induced chemokine expression varies between portal and sinusoidal vessels. Chemokines CXCL9 (Mig), CXCL10 (IP-10), and CXCL11 (I-TAC) are detected on sinusoids in association with liver inflammation, whereas relatively little induction of CCL5 (RANTES), CCL2 (MCP-1) or IL-8 is observed. By contrast, elevated levels of CCL5 (RANTES), CCL3 (MIP-1a), CCL2 (MCP-1), and CCL4 (MIP-10) have been detected on the portal vessels. Although the reasons for these differences are still unclear, it may reflect that the sinusoidal endo-thelium is fundamentally distinct from the portal endothe-lium. In fact, these observations may suggest a selective process for regional leukocyte recruitment during liver injury.

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Essentials of Human Physiology

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