Liver Constitution

The liver is formed by parenchymal cells, that is, hepato-cytes, and nonparenchymal cells. In contrast to hepatocytes that occupy almost 80 percent of the total liver volume, nonparenchymal liver cells occupy only 6 percent. Notably, it is the nonparenchymal cells of the liver that regulate an inflammatory response. For the following section we recommend reviews [1-3].

Endothelial Cells

Liver endothelial cells line the portal venules as well as the sinusoids. Whereas the endothelium of the portal venules can be likened to endothelium in other parts of the body, the sinusoidal endothelial cells are morphologically unique. The sinusoidal endothelial cells are characterized by an absence of tight junctions between cells, by a lack of basal lamina, and by the presence of open fenestrations that are arranged into characteristic sieve plates. These cells perform an important filtration function, as these small fenestrations allow free diffusion of many small substances between the blood and the hepatocyte surface. Sinusoidal endothelial cells have also been shown to endocytose many ligands including glycoproteins, components of the extracellular matrix (such as hyaluronate, collagen fragments, and fibronectin) and immune complexes. Sinusoidal endothelial cells may function as antigen-presenting cells in the context of both MHC-I and MHC-II restriction and are also active in the secretion of cytokines, eicosanoids, (i.e., prostanoids and leukotrienes), endothelin-1, nitric oxide, and some extracellular matrix components.

Kupffer Cells

Kupffer cells are intrasinusoidally located tissue macrophages (Figure 1) and have endocytic and phagocytic capabilities. Hepatic macrophages are in constant contact with gut-derived portal blood. Exposure of Kupffer cells to bloodborne pathogens (e.g., endotoxin) can lead to the intensive production of inflammatory mediators and the formation of liver injury. Liver macrophages modulate immune responses via antigen presentation and interaction with T cells. Among the many inflammatory mediators produced by Kupffer cells are reactive oxygen species, eicosanoids, nitric oxide, carbon monoxide, cytokines (TNFa), and chemokines [CXCL10 (IP-10) and CXCL9 (Mig)]. The activation of these cells identifies them as regulators of the early phase of liver inflammation and an important part in innate immune defense.

Hepatic Stellate Cells

Hepatic stellate cells are present in the perisinusoidal space. They are positioned with their well-branched cyto-plasmic processes in close proximity to the endothelial cells (Figure I). In the normal liver, hepatic stellate cells control turnover of extracellular matrix and are important in regulating the contractility of sinusoids. In the event of hepato-cyte damage, stellate cells transform into myofibroblast-like

Endothelial Cell Liver

Flgure 1 The leukocyte recruitment cascade. Fast-moving leukocytes in the bloodstream tether and roll on activated endothelium via interactions between adhesion molecules. Chemokines or other proinflammatory mediators released by various sources within the tissue are presented on the endothelium to rolling leukocytes, resulting in firm adhesion. Leukocyte transmigration across the endothelium and entry into inflamed tissue ensues. (see color insert)

Flgure 1 The leukocyte recruitment cascade. Fast-moving leukocytes in the bloodstream tether and roll on activated endothelium via interactions between adhesion molecules. Chemokines or other proinflammatory mediators released by various sources within the tissue are presented on the endothelium to rolling leukocytes, resulting in firm adhesion. Leukocyte transmigration across the endothelium and entry into inflamed tissue ensues. (see color insert)

Table I Adhesion Molecules and Chemokines Upregulated during Hepatic Inflammation.

Inflamed portal vessels

Inflamed sinusoids

ICAM-1

++

+

VCAM-1

+

+

VAP-1

+

+

PECAM-1

+

-

P-selectin

+

-

E-selectin

+

-

CCL2 (MCP-1)

++

+

CCL3 (MIP-1a)

++

+

CCL4 (MIP-1b)

++

+

CCL5 (RANTES)

++

+

IL-8

++

++

CXCL9 (Mig)

+

++

CXCL10 (IP-10)

+

++

CXCL11 (I-TAC)

+

++

cells and mediate the fibrotic response during inflammation. Activated stellate cells, like Kupffer cells, are potent sources of several chemokines including CXCL-10 (IP-10) and CCL-2 (MCP-1).

Lymphocytes

Intrahepatic lymphocytes comprise 25 percent of non-parenchymal cells in the normal liver (Figure 1). In contrast to peripheral blood, the major lymphoid population in the normal liver are pit cells (i.e., NKT cells, 30%), then T cells (20% TCR-ab and 10% TCR-gS), NK cells (20%), and very few B lymphocytes (5%). Natural killer T cells are a unique population of cells that express both CD3 and NK1 on their cell surface, secrete IL-2, IL-4, and IFNg, and recognize antigen in association with CD1. After NKT cells, the predominant intrahepatic T cells are CD8+. Notably, this predominance of CD8+ T cells in the liver differs from the CD4+ T cell majority observed in peripheral blood and spleen. CD8+ T cells, NKT cells, and NK cells all possess cytotoxic activity. Activated CD8+ T cells can be retained by the liver via their interaction with sinusoidal endothelial cells. These "trapped" activated T cells can then cause liver injury by releasing inflammatory cytokines and by apoptos-ing. Alternatively, circulating lymphocytes can be activated within the liver by Kupffer cells or hepatocytes. prior to their "activation-induced" cell death, these nonspecifically trapped T cells can also mediate liver damage by secreting mediators of inflammation (e.g., IL-12 and IFNg).

Neutrophils

Neutrophils are an essential component of innate host resistance and the adaptive responses to inflammation.

Although neutrophils constitute a relatively small percentage (1 to 2%) of the nonparenchymal liver cells in a normal (uninfected) mouse, a dramatic tenfold to twentyfold increase in neutrophils occurs within 2 hours following viral infection. previous observations suggest that neutrophils are the first cell type to arrive at sites of inflammation and as such form the first line of immune defense. In response to chemotactic factors released at inflammatory sites, neu-trophils migrate from the bloodstream through the vascular endothelium and adhere to parenchymal cells (Figure 1). Once at the inflammatory site, neutrophils can act as effector cells in an attempt to resolve the inflammation. Alternatively, neutrophils may be cytotoxic and cause necrotic tissue destruction by releasing proteases or reactive oxygen species. Neutrophils can also release chemokines such that more inflammatory cells are recruited to the afflicted site. A detrimental effect of neutrophils in acute and chronic liver disease processes has been shown in hepatic ischemia-reperfusion injury, endotoxemia, sepsis, and alcoholic hepatitis.

Taken together, the unique structure and constitution of the liver, such as the open fenestrations and position of the Kupffer cells, dictate that the barriers against inflammation differ from those in other parts of the body. Indeed, it has repeatedly been shown that inflammatory mediators have easy access to hepatocytes.

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