Reticuloendothelial Blockade

In studies of the physiological and pathophysiological roles of the RES, depression or blockade of the granulopectic activity of this system has attracted considerable attention. Among substances effectively depressing the reticuloendothelial activity are materials with different physicochemical properties. For example, various colloids [19], steroids such as cortisone [20], esters of fatty acids such as methyl palmitate [21], and liposome-encapsulated clodronate [22], Different theories have been suggested to explain the mechanisms of action of these materials.

Our experiments [23] have demonstrated that rare earth metal salts, among them gadolinium chloride (GdCl3), depress the reticuloendothelial activity and inhibit or completely abolish the effects of some reticuloendothelial stimulants. Our histological studies showed that the reticuloendothelial blockade induced by GdCI, is primarily due to the depression of the phagocytic activity by Kupffer cells [24], selectively depressing [25] or eliminating [26] large Kupffer cells.

Several studies have revealed that not only is the bulk of the intravenously injected particulate matter, colloidal particles, or cellular antigen taken up by the Kupffer cells, but the functional state of these cells strongly influences their distribution among the organs of the RES, which may have functional consequences [25,27],

Macrophages are the body's "alarm" cells that synthesize and excrete highly reactive materials, such as the superoxide anion, hydrogen peroxide, nitric oxide, eicosanoids, peptide mediators and proteolytic enzymes. These biologically active materials are very important in killing bacteria and tumour cells. However, macrophages not only act as a first line of defence but also have pivotal roles in regulating the immune response. The "over"-activation of macrophages and the excessive release of macrophage-derived destructive and immunosuppressive products may contribute to organ damage and the development of "multiple organ failure" in severe stress and injuries such as shock states [28],

Recent studies from many laboratories, including our own, have shown that the Kupffer cell blockade induced by GdCl3 modifies the immune response [29], exerts protective effects on anaphylactic [30], and endotoxic/septic shock [31,32], and decreases the liver-damaging effects of several hepatotoxins [33-35] and ischaemic-reperfusion [36.

Hepatic macrophages (Kupffer cells) account for approximately 15% of the total number of liver cells, and they account for 80-90% of the resident macrophages in the entire body [37]. Kupffer cells are located on the inside of the sinusoidal wall and they are found predominantly in the periportal region, which may represent the best location for these cells to exhibit their endo-cytic role for blood-borne materials entering the liver. Kupffer cells exhibit vigorous phagocytic activity and produce many kinds of soluble mediators such as cytokines, prostanoids, oxygen radicals, and proteases. In response to septic stimuli, hepatic macrophages are activated and release monokines, such as IL-1 and TNF-a. The secreted monokines then activate circulating leukocytes as well as sinusoidal endothelial cells and induce ICAM-1 expression. The resultant leukocyte adhesion to the endothelium disturbs the sinusoidal microcirculation and causes tissue damage by injurious mediators such as oxygen radicals, proteases, prostanoids, and other substances released from activated leukocytes [38],

Recent studies have elucidated the mechanisms by which GdCI.-induced Kupffer cell blockade protects against a variety of hepatotoxic processes. GdCl3 is most likely protective because it prevents the release of inflammatory cytokines and toxic oxygen radicals produced by activated Kupffer cells [39]. The causal roles of these mechanisms have been shown to be important in the prevention of hepatotoxic injuries caused by hepatotoxins, such as carbon tetrachloride and alcohol [40,41 ], or liver injuries associated with ischaemia reperfusion [42], liver transplantation [43] and sepsis [44],

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