Aspects of the interaction between cadmium and the acute inflammatory response.

The main aims of this thesis were to establish whether an acute inflammatory response is provoked in rats by the subcutaneous administration of cadmium, and to evaluate the possible role that such a response might play in the alterations in metal homeostasis and the development of anaemia which accompanies the use of this model of cadmium intoxication. An intense local reaction to the subcutaneous administration of cadmium was found. Many of the systemic changes, most notably in haematological parameters and in levels of iron, copper and plasma proteins, mimicked those seen in the acute inflammatory response. Possible causes of the resultant anaemia are discussed and inflammation is implicated as a predominant factor in its development. The results suggest that many of the effects which in previously published work have been attributed to a direct interaction of cadmium with the system under investigation, may in fact be secondary consequences of cadmium-induced inflammation. Comparison of the effects of subcutaneous administration of cadmium and other selected metal salts with changes occurring in two recognised models of acute inflammation revealed marked differences in the local tissue reaction to different substances as well as in the magnitude of various components of the systemic response. The oedematous, necrotic and extensively destructive nature of the cadmium-induced lesion has been highlighted and shown to be partially alleviated by pre- and simultaneous treatment with zinc. Explanations for this protective phenomenon are offered, based on possible target sites of cadmium, particularly in terms of interaction with zinc-dependent processes. With a view to understanding the mechanisms involved in acute cadmium toxicity, luminol-amplified chemiluminescence, which is indicative of free radical formation and the production of reactive oxygen species, was measured directly from intact tissue samples. Inflamed tissue sampled from subcutaneous sites of cadmium administration emitted substantially more chemiluminescence than noninflamed tissue or tissue from sites to which other metals or turpentine was administered. It was demonstrated that intact tissue samples can also be used to assess free radical generation, as detected by chemiluminescence, during in vitro treatment. A pronounced dose-related response was seen with cadmium which could be inhibited by various pretreatment procedures, such as incubation with zinc or certain metal chelators. The significance of these results in relation to the mechanism of toxic action of cadmium as well as to the potential use of this chemiluminescence technique is discussed