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Particulate Matter in Cigarette Smoke Alters Iron Homeostasis to Produce a Biological Effect

¹ National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina; ² Department of Medicine, Columbia University, New York, New York; ³ Center for Health and the Environment, University of California, Davis, California

Correspondence and requests for reprints should be addressed to Andrew J. Ghio, M.D., Human Studies Division, NHEERL, USEPA, Research Triangle Park, NC 27711. E-mail: ghio.andy{at}epa.gov

Rationale: Lung injury after cigarette smoking is related to particle retention. Iron accumulates with the deposition of these particles.

Objectives: We tested the postulate that (1) injury after smoking correlates with exposure to the particulate fraction of cigarette smoke, (2) these particles alter iron homeostasis, triggering metal accumulation, and (3) this alteration in iron homeostasis affects oxidative stress and inflammation.

Methods: Rats and human respiratory epithelial cells were exposed to cigarette smoke, filtered cigarette smoke, and cigarette smoke condensate (the particulate fraction of smoke), and indices of iron homeostasis, oxidative stress, and inflammatory injury were determined. Comparable measures were also evaluated in nonsmokers and smokers.

Measurements and Main Results: After exposure of rats to cigarette smoke, increased lavage concentrations of iron and ferritin, serum ferritin levels, and nonheme iron concentrations in the lung and liver tissue all increased. Lavage ascorbate concentrations were decreased, supporting an oxidative stress. After filtering of the cigarette smoke to remove particles, most of these changes were reversed. Exposure of cultured respiratory epithelial cells to cigarette smoke condensate caused a similar accumulation of iron, metal-dependent oxidative stress, and increased IL-8 release. Lavage samples in healthy smokers and smoking patients with chronic obstructive pulmonary disease revealed elevated concentrations of both iron and ferritin relative to healthy nonsmokers. Lavage ascorbate decreased with cigarette smoking. Serum iron and ferritin levels among smokers were increased, supporting systemic accumulation of this metal after cigarette smoke exposure.

Conclusions: We conclude that cigarette smoke particles alter iron homeostasis, both in the lung and systemically.

Key Words: smoking • ferritin • oxidants • chronic obstructive pulmonary disease

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The mechanism(s) for tissue injury after cigarette smoking is not known. Reasons for the persistence of risk for disease after cessation of smoking similarly is not recoganized. What This Study Adds to the Field This investigation supports a mechanism of tissue injury after disruption of iron homeostasis (both in the lung and systemically) by cigarette smoke particles. Accumulated iron then catalyzes oxidative stress and biological effect.

 

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