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Suppressive Oligodeoxynucleotides Inhibit Silica-Induced Pulmonary Inflammation

Takashi Sato^*, Takeshi Shimosato^*, W. Gregory Alvord and Dennis M. Klinman^1,*

^* Laboratory of Experimental Immunology and Data Management Services, Inc., National Cancer Institute, Frederick MD, 21702

Inhalation of silica-containing dust particles induces silicosis, an inflammatory disease of the lungs characterized by the infiltration of macrophages and neutrophils into the lungs and the production of proinflammatory cytokines, chemokines, and reactive oxygen species (ROS). Synthetic oligodeoxynucleotides (ODN) expressing "immunosuppressive motifs" were recently shown to block pathologic inflammatory reactions in murine models of autoimmune disease. Based on those findings, the potential of suppressive ODN to prevent acute murine silicosis was examined. In vitro studies indicate that suppressive ODN blunt silica-induced macrophage toxicity. This effect was associated with a reduction in ROS production and p47phox expression (a subunit of NADPH oxidase key to ROS generation). In vivo studies show that pretreatment with suppressive (but not control) ODN reduces silica-dependent pulmonary inflammation, as manifest by fewer infiltrating cells, less cytokine/chemokine production, and lower levels of ROS (p < 0.01 for all parameters). Treatment with suppressive ODN also reduced disease severity and improved the survival (p < 0.05) of mice exposed to silica.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Address correspondence and reprint requests to Dr. Dennis M. Klinman, Building 567, Room 205, National Cancer Institute, Frederick, MD 21702. E-mail address: klinmand{at}mail.nih.gov

² Abbreviations used in this paper: BAL, bronchoalveolar lavage; ODN, oligodeoxynucleotide; ROS, reactive oxygen species; MTT, [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide]; LDH, lactase dehydrogenase; phox, phagocytic oxidase.