TNFα and increased chemokine expression in rat lung after particle exposure

Abstract

Macrophage inflammatory protein 2 (MIP-2) and CINC (Cytokine-Induced-Neutrophil-Chemoattractant) are members of the chemokine family of inflammatory and immunoregulatory cytokines. MIP-2 and CINC exhibit potent neutrophil chemotactic activity and are thought to be key mediators of inflammatory cell recruitment in response to tissue injury and infection. In the present studies, we examined the potential involvement of MIP-2 and CINC in particle-elicited inflammation in the rat lung and the role of TNFα in particle-induced chemokine expression. Acute intratracheal instillation exposure of F344 rats to α quartz or titanium dioxide was shown to markedly increase steady-state levels of MIP-2 and CINC mRNA in lung tissue; a response which was associated with a significant increase in neutrophils in the bronchoalveolar lavage fluid. Additional studies demonstrated that acute inhalation of crocidolite fibers by rats also induced increased MIP-2 and CINC expression. Since previous studies had demonstrated that TNFα stimulates MIP-2 and CINC expression in vitro and that particle exposure induces TNFα production in rat lung we examined the role of TNFα in a quartz-induced MIP-2 gene expression. We demonstrated that passive immunization of mice against TNFα markedly attenuated the increased lung MIP-2 mRNA seen in response to a quartz inhalation. Collectively, these findings suggest that the chemokines MIP-2 and CINC play a role in neutrophil recruitment to the rat lung after particle exposure and indicate that particle-induced expression of these chemokines is mediated, at least in part, by production of TNFα.