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Am. J. Respir. Cell Mol. Biol., Volume 19, Number 3, September, 1998 366-378

Copper-dependent Inflammation and Nuclear Factor-kappa B Activation by Particulate Air Pollution

Thomas Kennedy, Andrew J. Ghio, William Reed, James Samet, John Zagorski, Jacqueline Quay, Jacqueline Carter, Lisa Dailey, John R. Hoidal, and Robert B. Devlin

Department of Internal Medicine, Carolinas Medical Center, Charlotte; National Health and Environmental Effects Research Laboratory, Environmental Protection Agency, Research Triangle Park; Center for Environmental Medicine and Lung Biology, University of North Carolina, Chapel Hill, North Carolina; Oral Infection and Immunity Branch, National Institute of Dental Research, Bethesda, Maryland; and Asthma Center, Primary Children's Hospital, Salt Lake City, Utah

Particulate air pollution causes increased cardiopulmonary morbidity and mortality, but the chemical determinants responsible for its biologic effects are not understood. We studied the effect of total suspended particulates collected in Provo, Utah, an area where an increase in respiratory symptoms in relation to levels of particulate pollution has been well documented. Provo particulates caused cytokine-induced neutrophil chemoattractant-dependent inflammation of rat lungs. Provo particulates stimulated interleukin-6 (IL-6) and IL-8 production, increased IL-8 messenger RNA (mRNA) and enhanced expression of intercellular adhesion molecule-1 (ICAM-1) in cultured BEAS-2B cells, and stimulated IL-8 secretion in primary cultures of human bronchial epithelium. Cytokine secretion was preceded by activation of the transcription factor nuclear factor-kappa B (NF-kappa B) and was reduced by treatment of cultures with superoxide dismutase, deferoxamine, or N-acetylcysteine. These biologic effects were replicated by culturing BEAS cells with quantities of Cu2+ found in Provo extract. IL-8 secretion by BEAS cells could be modified by addition of normal constituents of airway lining fluid to the culture medium. Mucin significantly reduced IL-8 secretion, and ceruloplasmin significantly increased IL-8 secretion and activation of NF-kappa B. These findings suggest that copper ions may cause some of the biologic effects of inhaled particulate air pollution in the Provo region of the United States, and may provide an explanation for the sensitivity of asthmatic individuals to Provo particulates that has been observed in epidemiologic studies.




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