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-κB, 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-κB may play a role in ozone-induced MCP-1 gene expression.

CCL7 and CXCL10 Orchestrate Oxidative Stress-Induced Neutrophilic Lung Inflammation

“…Exposure of animals to O 3 has been shown to increase monocyte chemotactic activity in bronchoalveolar fluid (21). This activity was inhibited by an Ab directed against CCL2 in a monocyte chemotaxis assay (21).…”

“…For example, Zhao et al (21) reported that 2 ppm O 3 induced CXCL1,2,3 (MIP-2) mRNA expression that peaked 4 h postexposure, whereas CCL2 mRNA levels peaked at 24 h postexposure. In the present study, the CXCL1,2,3 (KC and MIP-2), CXCL10, CCL3, CCL7, and CCL11 were up-regulated at 0 h postexposure, whereas only CCL3, CCL7, and CXCL10 were still up-regulated 18 h postexposure, indicating differences in the kinetics of different chemokine expression.…”

“…Exposure of animals to O 3 has been shown to increase monocyte chemotactic activity in bronchoalveolar fluid (21). This activity was inhibited by an Ab directed against CCL2 in a monocyte chemotaxis assay (21). The in vivo role of chemokines was assessed by Koto et al (12), who reported that in vivo administration of an Ab to cytokine-induced neutrophil chemoattractant inhibited neutrophilic but not macrophagic inflammation.…”

“…Earlier studies have reported that O 3 up-regulates CXCL-8 mRNA expression and protein production in the lungs of animals and humans exposed to O 3 (19,20). In addition to CXCL-8, O 3 has been shown to induce other CXC chemokines, such as members of the Gro family of CXCL1,2,3 and CXCL10 (21)(22)(23). Other investigators have reported that O 3 up-regulates CC chemokines such as CCL2, CCL3, and CCL11 (21,23).…”

“…In addition to CXCL-8, O 3 has been shown to induce other CXC chemokines, such as members of the Gro family of CXCL1,2,3 and CXCL10 (21)(22)(23). Other investigators have reported that O 3 up-regulates CC chemokines such as CCL2, CCL3, and CCL11 (21,23). Even though O 3 exposure has been shown to up-regulate these chemokines, few studies have evaluated the in vivo role of these chemokines, which mediate O 3 -induced airway inflammation (12).…”