Role of macrophages and inflammatory mediators in chemically induced toxicity

Macrophages are critical cellular effecters of nonspecific host defense. Th ey are also potent secretory cells releasing an array of mediators includin g proinflammatory and cytotoxic cytokines and growth factors, bioactive lip ids, hydrolytic enzymes and reactive oxygen and nitrogen intermediates, eac h of which has been implicated in tissue injury. The research in our labora tories has focused on analyzing the role of macrophages in chemically induc ed injury in the lung and the liver. In both these tissues, a localized acc umulation of macrophages is observed following toxicant exposure. This is d irectly correlated with the generation of cytotoxic inflammatory mediators at these sites. Moreover, when macrophage functioning is blocked, pulmonary and hepatic injury induced by toxicants such as ozone or acetaminophen is prevented. These findings provide direct support for our hypothesis that ma crophages contribute to tissue injury. Approaches using pharmacologic inhib itors and transgenic animals are currently being used to evaluate the speci fic macrophage-derived products involved in the pathogenic process. Our res ults suggest that the extent to which a particular mediator contributes to injury depends on the nature of the toxicant, the target tissue, and quanti ties of the mediator produced. (C) 2001 Elsevier Science Ireland Ltd. All r ights reserved.