Chemokine regulation of ozone-induced neutrophil and monocyte inflammation.

Abstract

Pulmonary inflammation has been observed in humans and in many animal species after ozone exposure. Inflammatory cell accumulation involves local synthesis of chemokines, including neutrophil chemoattractants such as macrophage inflammatory protein-2 (MIP-2), and monocyte chemoattractants, such as monocyte chemoattractant protein-1 (MCP-1). To better understand the mechanism of ozone-induced inflammation, we exposed mice and rats to ozone for 3 h and measured MIP-2 and MCP-1 gene expression. In C57BL/6 mice, steady-state mRNA levels for MCP-1 in the lung increased at 0.6 parts/million (ppm) ozone and were maximal at 2.0 ppm ozone. After exposure to 2 ppm ozone, MIP-2 mRNA levels peaked at 4 h postexposure, whereas MCP-1 mRNA levels peaked at 24 h postexposure. Neutrophils and monocytes recovered in bronchoalveolar lavage fluid peaked at 24 and 72 h, respectively. The accumulation of monocytes was thus delayed relative to that of neutrophils, consistent with the sequential expression of the corresponding chemokines. The role of MCP-1 in monocyte accumulation was evaluated in greater detail in rats. Ozone caused an increase in monocyte chemotactic activity in bronchoalveolar fluid that was inhibited by an antibody directed against MCP-1. Ozone-induced MCP-1 mRNA levels were higher in lavage cells than in whole lung tissue, indicating that lavage cells are an important source of MCP-1. In these cells, nuclear factor-kappa B, a nuclear transcription factor implicated in MCP-1 gene regulation, was also activated 20-24 h after ozone exposure. These findings indicate that monocyte accumulation subsequent to acute lung injury can be mediated through MCP-1 and that nuclear factor-kappa B may play a role in ozone-induced MCP-1 gene expression.