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Diesel Exhaust Particles Enhance Lung Injury Related to Bacterial Endotoxin through Expression of Proinflammatory Cytokines, Chemokines, and Intercellular Adhesion Molecule-1

National Institute for Environmental Studies, Tsukuba; First Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto; Department of Health Science, Oita University of Nursing and Health Sciences, Oita; and Department of Pharmacology, Kobe Pharmaceutical University, Kobe, Japan

Correspondence and requests for reprints should be addressed to Hirohisa Takano, Pathophysiology Research Team, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba 305-0053, Japan. E-mail: htakano{at}nies.go.jp

Epidemiologic studies demonstrate acute and serious adverse effects of particulate air pollution on respiratory health, especially in people who are susceptible to bacterial infection. However, the underlying mechanism remains to be elucidated. To provide experimental evidence for the epidemiologic data, we determined the effects of diesel exhaust particles (DEP), major participants in particulate pollutants, on lung injury related to bacterial endotoxin in mice. Intratracheal instillation of DEPs synergistically enhanced lung injury related to endotoxin from gram-negative bacteria, which was characterized by neutrophil sequestration, interstitial edema, and alveolar hemorrhage. In the presence of endotoxin, DEPs further activated the nuclear translocation of p65 subunit of nuclear factor-B (NF-B) in the lung and increased the lung expression of intercellular adhesion molecule-1, interleukin-1ß, macrophage chemoattractant protein-1, keratinocyte chemoattractant (KC), macrophage inflammatory protein-1, and Toll-like receptors. DEPs given alone increased the lung expression of Toll-like receptor 4 and the nuclear localization of p50 subunit of NF-B. The combined exposure to DEPs and endotoxin decreased nuclear localization of CCAAT/enhancer binding protein ß. These results provide the first experimental evidence that DEPs enhance neutrophilic lung inflammation related to bacterial endotoxin. The enhancement is mediated by the induction of proinflammatory molecules, likely through the expression of Toll-like receptors and the activation of p65-containing dimer(s) of NF-B, such as p65/p50.

Key Words: acute lung injury • chemokines • transcription factors • lipopolysaccharide • diesel exhaust particles

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