Am. J. Respir. Cell Mol. Biol., Volume 20, Number 2, February, 1999 189-198

Superoxide Mediates Cigarette Smoke-Induced Infiltration of Neutrophils into the Airways through Nuclear Factor-B Activation and IL-8 mRNA Expression in Guinea Pigs In Vivo

Masanori Nishikawa, Nobumasa Kakemizu, Takaaki Ito, Makoto Kudo, Takeshi Kaneko, Motoyoshi Suzuki, Naoko Udaka, Hirotada Ikeda, and Takao Okubo

First Department of Internal Medicine and Department of Pathology, Yokohama City University School of Medicine, Yokohama, Japan

We examined the hypothesis that superoxide mediates infiltration of neutrophils to the airways through nuclear factor (NF)-B and interleukin-8 (IL-8) after acute exposure to cigarette smoke (CS) in vivo. Male Hartley strain guinea pigs were exposed to air or 20 puffs of CS and killed 5 h after the exposure. The differential cell count of bronchoalveolar lavage fluid and specific myeloperoxidase enzyme assay demonstrated that acute exposure to CS caused neutrophil accumulation to the airways and parenchyma, respectively. Acute exposure to CS increased DNA-binding activity of NF-B in the lung. Acute exposure to CS also increased IL-8 messenger RNA (mRNA) expression in the lung. Pretreatment of guinea pigs with recombinant human superoxide dismutase (rhSOD) aerosols reduced the CS-induced neutrophil accumulation to the airways. Both activation of NF-B and increased IL-8 mRNA expression were also inhibited by the pretreatment of rhSOD aerosols. Strong immunoreactivities for p65 and p50 were detected in the nuclei of alveolar macrophages after acute exposure to CS. The signal for IL-8 mRNA expression was demonstrated in the alveolar space after acute exposure to CS. Neither significant immunoreactivities for p65 and p50 nor IL-8 mRNA signals were observed in airway epithelium. These observations suggest that acute exposure to CS initiates superoxide-dependent mechanism that, through NF-B activation and IL-8 mRNA expression, produces infiltration of neutrophils to the airways in vivo. It was also suggested that the alveolar macrophage is one potential source of NF-B activation and IL-8 mRNA expression after acute exposure to CS.

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