The objective of the proposed research is to examine the effects of trace heavy metals, specifically cadmium and lead, on wound healing. The wound healing process is an organized chain of events at the cellular and molecular level involving 3 main components: macrophages, fibroblasts and collagen synthesis. The literature demonstrates that heavy metals can modulate activity in each of these components although the studies generally do not involve wound healing models. We demonstrated that low level cadmium exposure affects the response to both skin isografts and allografts and hypothesize that this is due to an effect on wound healing. Therefore, we propose to systematically examine the effect of cadmium and lead on the various cellular and biochemical responses involved in wound healing including those of macrophages (phagocytosis, collagenase secretion, and production of factors modulating fibroblast function) and fibroblasts (growth, proliferation, collagen synthesis and response to macrophage-derived factors) as well as on the activity of a number of enzymes involved in collagen synthesis. These studies will be performed utilizing wounded and normal skin, fibroblasts derived from skin explants, the 3T3 fibroblast cell line and peritoneal macrophages. Metal exposure will be in vivo (via drinking water) and in some cases, the effects of in vitro exposure will also be examined. The effects of metals will also be examined in situ through a histopathologic examination of cellular infiltration, revascularization and collagen deposition, measurement of collagen synthesis by wounded and non-wounded skin, and revascularization of grafted skin. These studies should contribute to an understanding of heavy metal toxicity at concentrations which may be encountered environmentally and thus help to understand a significant public health problem.
