Gadolinium chloride

Several chemicals are able to suppress the phagocytic capability of macrophages to some extent. A strong blockade of phagocytosis could be achieved by treatment of animals with 'rare earth metals' such as gadolinium (6). In addition to blocking of phagocytosis, intravenous injection of gadolinium chloride in rats also eliminated a part of the Kupffer cell population in the liver, namely the large macrophages situated in the periportal zone of the liver acinus, but not those in the rat spleen (7). However, intravenous administration of gadolinium chloride in mice did not eliminate Kupffer cells in their liver and addition of gadolinium chloride to cultures of mouse peritoneal macrophages did not affect these cells. Moreover, frequent mitotic figures ofhepatocytes in the liver of mice injected with gadolinium chloride suggested a proliferative effect on non-phagocytic cells. In contrast to particulate agents and polymerized complexes, gadolinium chloride, as a small molecule, could have the advantage of a relatively easy transport through capillary walls. For that reason, intravenously injected gadolinium chloride could be able to reach macrophages in many organs apart from liver and spleen. However it has been demonstrated that intravenously injected gadolinium chloride did not affect alveolar macrophages and interstitial macrophages in the rat lung.

Although animals treated with gadolinium chloride revealed a significantly lower phagocytic activity of Kupffer cells, a pronounced rise in serum cytokine activity (TNFa and IL-1) was detected (8). Obviously inhibition of phagocytosis was closely related to stimulation of cytokine production, a phenomenon also described for treatment with silica, carrageenan, and dextran sulfate.

2.3 Anti-macrophage antibodies and receptor antagonists

Different surface receptors on macrophages, such as scavenger receptors, complement and Fc receptors, sialoadhesin (SER) receptors, and mannose receptors play a role in phagocytosis. As a consequence, both receptor antagonists and antibodies directed against these receptors should be able to suppress receptor-mediated phagocytosis for at least a limited period of time. However it may be expected that macrophages will rapidly internalize and hydrolyse any blocking molecules so that suppression of phagocytosis will last for a short period of time only and will require high doses of the blocking molecules. Nevertheless, a dose-dependent blockade of phagocytosis by mannose and mannose derivatives was shown for macrophages in the rat spleen. In practice, blocking of macrophages by mannose or mannose derivatives has not been applied. Also polyclonal antimacrophage antibodies have the capability to suppress phagocytosis for a certain period of time, and this approach has been used in several studies aimed at the unravelling of macrophage function. Since most studies in which anti-macrophage antibodies were applied for blocking of macrophages were performed well before it was found that macrophages are responsible for the production of a large panel of cytokines, the latter aspect has not been investigated in these studies.

2.4 Competition

Administration of a high dose of particles that will be ingested by macrophages may lead to saturation of their phagocytosis capability. In early studies on the role of phagocytosis in the induction of antibody responses, India ink (colloidal carbon particles), or other finely divided compounds such as saccharated iron oxide, thorotrast, or polystyrene latex were used as agents for blocking of phagocytosis. However these particles can not be degraded by macrophages and will be ingested by new macrophages as soon as they are released from dying macrophages.

In the contrary, liposomes are artificially prepared spheres, that can be degraded by macrophages. The natural fate of liposomes when administered in vivo, is phagocytosis followed by intracellular degradation of the liposomal phospholipid bilayers as a result of the activity of lysosomal phospholipases. It has been demonstrated that liposome suspensions are also able to saturate the phagocytic activity of macrophages in a way similar to that described for finely suspended carbon particles (9). One should be aware that, dependent on their composition, liposomes may alter the structure and characteristics of cell membranes of macrophages after their internalization. However, liposomes can be prepared from phospholipids that are practically inert; for instance they can be made up merely of lecithin (phosphatidylcholine).

Contrary to the blocking of phagocytosis by agents such as silica, carrageenan, dextran sulfate, and gadolinium chloride, liposomes did not stimulate the basic or lipopolysaccharide-induced production of proinflammatory cytokines and/or nitric oxide (NO) by macrophages. So, the application of liposomes as a phagocytosis blocking agent offers the advantage of minimum side-effects on cytokine production and secretion.

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