© 2004 American Thoracic Society DOI: 10.1165/rcmb.F284
Cigarette Smoke in ResearchUniversity of Nebraska Medical Center, Omaha, Nebraska Address correspondence to: Stephen I. Rennard, M.D., University of Nebraska Medical Center, 985885 Nebraska Medical Center, Omaha, NE 68198-5885. E-mail: srennard{at}unmc.edu The burning tobacco on the end of a cigarette heats the air drawn through it. The hot air then passes over the unburned tobacco in the cigarette rod, causing nicotine and other volatile components to evaporate. As the air cools while being drawn through the cigarette, some of these volatile components, including nicotine, condense onto smoke particles. A smoker inhales this nicotine-rich aerosol, which happens to have a mean particle diameter in the submicron range, permitting efficient alveolar deposition and subsequent extremely rapid absorption into the systemic blood. In addition to nicotine, a burning cigarette generates as many as 6,000 other compounds, many of which are toxic. Most are generated by the burning tobacco on the end of the cigarette. The absolute and relative production of these many substances depends on a number of factors: importantly, the temperature and duration of the burn. In addition, compounds present in cigarette smoke undergo complex chemical reactions. Many are extremely short-lived. Others condense on the cigarette rod, where they can be re-extracted or rereacted. Because these processes vary with smoking topography (i.e., how the cigarette is smoked, number of puffs, puff volume, puff duration, etc.), the toxins generated can vary from puff to puff. Certainly, the exposures experienced by one smoker differ considerably from those of another (1). This variability has greatly confounded and limited attempts to quantify cigarette "yields." It also poses major problems for investigators studying the toxic effects of cigarette smoke. Cigarette smoking is a major contributing factor in the development of a large number of fatal and debilitating disorders (2). Understanding the mechanisms by which smoking contributes to disease has been, and will remain, a major research focus. Several approaches have been used to evaluate cigarette smoke in this regard. One approach has been to capture the smoke emitted from a cigarette by bubbling it through an aqueous solution (3). Such preparations, termed cigarette smoke extract or, more pejoratively, "liquid smoke," have been widely used as sources of material to add to various systems, particularly in vitro assays. Such preparations have the serious disadvantage of losing volatile and rapidly reactive components. Particulate components are captured, but may be subsequently lost if the "extract" is processed, for example, by filtration to achieve sterility. A variety of chemical changes, moreover, can take place with storage. Standardizing such preparations is problematic even if experimental reproducibility is generally achieved. The exposure of cells to smoke in culture requires model systems with trade-offs. The fact that smoke extracts differ from "routine" smoke is a limitation. However, in vivo cells are not exposed to "smoke," but rather to components of smoke that have been extracted into biological fluids. Reductionist approaches that evaluate defined concentrations of specific components present in smoke are also problematic. Although the toxicity of individual components can be assessed, it is likely that the biological response to complex mixtures such as cigarette smoke is not the sum of multiple independent toxicities. In vitro assays, using some type of smoke preparation, will, without doubt, remain important tools in the assessment of cigarette smoke–induced toxicity. In vitro cell culture studies using cigarette smoke extracts are likely to remain useful model systems. In vivo studies pose different sets of problems. It is much less plausible that exposure of animals to smoke extracts is a reasonable means of evaluating toxicity. Exposing animals to smoke, however, is no simple matter either. Few animal species smoke cigarettes the way humans do. Various smoking machines are frequently used. Breathing smoke generated by a machine, however, is more like passive smoke exposure than active smoking. This is more of a problem for "whole-body exposures," but also pertains to nose-only devices. Moreover, as the yield of cigarettes depends importantly on the smoking regimen used (4), the exposures from such machines will be determined, in large part, by arbitrary methodologic choices. Other animal species, moreover, do not breathe in the same manner as do people. Rodents, for example, are obligate nose breathers, resulting in a very different pattern of particle filtration in the nares and upper respiratory tract than that experienced by mouth breathing (i.e., cigarette smoking humans). Thus, whereas use of smoke is much more plausible than smoke extract as an exposure for animals in in vivo studies, it must also be regarded as a model system that imperfectly models human exposures. Despite these noted methodologic limitations, studies using these techniques have provided great insight and are likely to continue to do so. Smoke, or, more properly, smoke extract, is capable of activating a variety of cell types, leading to production of a variety of mediators that have been suggested to play important pathophysiologic roles in various aspects of smoke-induced toxicity. Smoke exposure of other animal species causes conditions that resemble human disease, and such model systems have been used to evaluate both the effects of specific genes in genetically modified animals and the potential therapeutic interventions. All such studies are model studies, the major purpose of which is to evaluate hypotheses relating to human disease. Only studies in humans smoking real cigarettes with real smoking topographies will serve as definitive tests of any of these hypotheses. Investigators need to be aware of the limitations of model systems. Recognizing limitations, however, should not be confused with discounting value. The categorical rejection of model systems because they imperfectly reproduce some aspect of human smoking is unscientific and unlikely to advance understanding of anything. Cautious interpretation of experimental results, recognizing limitations of specific systems used, is essential if understanding of the pathogenesis of cigarette smoke–induced disease is to be advanced and if a scientific basis is to be established that can help mitigate the scourge of illness caused by cigarette smoking.
Conflict of Interest Statement: S.I.R. has consulted for the following companies, for which he received fees: Almiral, Altana, Amersham, Array Biopharma, AstraZeneca, Aventis, Boehringer Ingelheim, Critical Therapeutics, GlaxoSmithKline ($14,000), Globomax, Intermune, Merck, Novartis, Ono, Otsuka, Roche, Sanofi, Scios, and Wyeth; he has received lecture fees from AstraZeneca ($13,500), GlaxoSmithKline ($33,000), and Pfizer; and he serves on advisory boards for Altana ($20,000) and Inspire ($5,000). He has received grants for clinical trials from Centocor ($64,000), GlaxoSmithKline ($731,000), Novartis ($78,000), Pfizer ($436,000), Roche ($30,000), and Sanofi ($758,000); and laboratory grants from AstraZeneca ($89,500), Centocor ($49,000), and GlaxoSmithKline ($120,000). S.I.R. has served on an advisory board of R.J. Reynolds, for which he received no compensation. Received in original form August 27, 2004
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Top
References
