The overall focus of the research in my laboratory is immunology. We are particularly interested in nonspecific immunity mediated by macrophages, which are critical cellular components of the host response to tissue injury. Although the involvement of macrophages in protecting against invading pathogens and tumor cells is well documented, recent studies from our laboratory have demonstrated that macrophages also have a dark side. Thus they can be activated to release excessive quantities of proinflammatory and cytotoxic mediators that actually promote tissue injury. An analysis of this process represents the main focus of our research. Two mouse models are being utilized to investigate the role of macrophages and inflammatory mediators in toxicity: the lung and the liver. In each of these tissues, we found that exposure of mice to xenobiotics is associated with localized accumulation of macrophages. Moreover, macrophages isolated from the lung or liver of animals treated with tissue specific toxicants are "activated" to release increased quantities of inflammatory mediators such as tumor necrosis factor alpha, nitric oxide and superoxide anion.
To analyze the role of these cytotoxic mediators in toxicity, both pharmacologic inhibitors and knockout mice are being utilized. Whereas in some model systems, both approaches result in similar results in others such as hepatic necrosis induced by acetaminophen administration, opposing results are obtained. Thus, in this model, anti-TNFα antibody prevents toxicity, while TNFα knockout mice were more sensitive to acetaminophen. These data suggest that there are limitations to the use of transgenic animals which may be related to compensatory alterations in cytotoxic mediators production and this is being investigated. Another aspect of our studies is to elucidate biochemical mechanisms mediating macrophage activation in the liver and the lung. This has involved investigations on signaling molecules such as MAP kinases, and transcription factors such as NFkB, C/EBP and AP-1. Much of our research has taken advantage of new technological developments in biochemistry, molecular biology and flow cytometry/image analysis.