In 2000 an estimated 4.8 million deaths worldwide were attributable to smoking (1). The major health hazards of tobacco use are well known and include cardiovascular disease, chronic obstructive pulmonary disease, lung cancer, and increased risk of infections (2). Immunosuppressive properties of tobacco smoke and effects on innate and adaptive immunity may contribute to the development of some of these diseases (3). Recent studies, however, also suggest that the same immunosuppressive properties may have beneficial effects on some inflammatory diseases, such as hypersensitivity pneumonitis, as noted by Blanchet and colleagues (pp. 903–909) in this issue of the Journal (3, 4).

Since the 1970s, numerous epidemiologic studies have shown that individuals with hypersensitivity pneumonitis or sarcoidosis are less likely to smoke compared with control subjects or the population at large (5–8). Other studies indicate that smokers have a lower serum antibody response to hypersensitivity pneumonitis-inducing agents (9). Collectively, these findings suggest that smoking may be protective or inhibit the development of granulomatous inflammation; this observation has not been well acknowledged by the medical community, probably for a number of reasons. First, the epidemiologic studies are associative and do not indicate a definite causal link between smoking and decreased risk of disease. Thus, decreased smoking could be an epiphenomenon or even a result of the development of respiratory symptoms or disease. Second, these studies do not provide a potential mechanism(s) by which cigarette smoke may inhibit the development of disease. Finally, clinicians who frequently confront the devastating and common clinical sequelae of tobacco abuse may be reluctant to acknowledge that tobacco, with all of its negative effects, could reduce the risk of granulomatous lung diseases. How would we counsel our patients with these diseases or with exposures that might increase the risk of disease?

The study by Blanchet and coworkers provides additional support and biological plausibility that smoking reduces the development of granulomatous lung disease (4). Using the antigen Saccharapolysora rectivirgula to induce granulomatous inflammation in mouse and cell line models of disease, the investigators demonstrate that simultaneous nicotine exposure reduces the bronchoalveolar lavage cellular response, including the total lavage white blood cell and lymphocyte cell count, the extent of lung inflammation on biopsy, and interferon-γ but not interleukin-10 mRNA expression in the lung. Using a macrophage cell line treated concomitantly with lipopolysaccharide or Saccharapolysora rectivirgula and nicotine, decreased tumor necrosis factor protein, and tumor necrosis factor, interleukin-10, and interferon-γ mRNA were observed.

Expanding on the epidemiologic studies, this study begins to evaluate possible mechanisms by which nicotine and, potentially, cigarette smoke may inhibit development of granulomatous lung disease. This study and others suggest that smoke and its components affect cellular constituents in bronchoalveolar fluid, with a relative increase in macrophages and a decrease in lymphocytes and dendritic cells (3, 4, 10, 11). Relevant cellular functions are likely impaired, as macrophages demonstrate decreased antigen phagocytosis and clearance and T cells display altered antigen-mediated signaling and proliferation, indicative of impaired cell-mediated immunity (3, 10, 12, 13). In mouse and cell line models for hypersensitivity pneumonitis in this study, nicotine altered the pattern of cytokine production (4). This change in the Th1/Th2 cytokine balance is thought to be crucial to the development of granulomatous lung disease and reflects another potential critical immunomodulatory effect of nicotine (3, 12, 14, 15).

There are a number of questions raised by the study of Blanchet and coworkers (4). What are the specific mechanisms vital to tobacco's immunosuppressive effects and its ability to inhibit hypersensitivity pneumonitis and sarcoidosis? Are there other nonimmunogenic effects of tobacco or nicotine, which reduce disease risk or development? Is nicotine the only agent in tobacco smoke that is able to inhibit the development of hypersensitivity pneumonitis? There are over 4,500 components of tobacco smoke. Acrolein, hydroquinone, catechol, and benzo[a]pyrene have demonstrated immunosuppressive effects in cell and animal models (3, 13, 15). Can other components of cigarette smoke alone or in combination completely abolish these granulomatous diseases or, as is noted in mice in this study and previous human studies, are these effects partial? In humans, might nicotine or cigarette smoke incompletely suppress the inflammatory response but make it difficult to obtain a definitive diagnosis? What happens to those who develop disease despite smoking? Epidemiologic studies suggest that smokers with hypersensitivity pneumonitis or sarcoidosis may have a more insidious and progressive form of the disease (6, 16). Long-term effects of nicotine or smoke on the mice in this model have not been reported to date.

Finally, the question we are pondering but are hesitant to ask: should we recommend smoking or nicotine as therapy for granulomatous lung diseases? Although Blanchet and coworkers suggest that we may want to consider nicotine as treatment for hypersensitivity pneumonitis, the studies to date do not support this approach (4). Primary prevention of disease with cigarette smoke or nicotine is not likely to be beneficial as there are significant risks associated with this therapy to treat a disease that develops in a fraction of those exposed. Moreover, both in this model and in human disease, nicotine or cigarette smoke does not completely abolish the granulomatous immune response (4–7, 11). Most importantly, we do not know whether nicotine or cigarette smoke is able to modulate granulomatous inflammation once started. The studies from humans with sarcoidosis and hypersensitivity pneumonitis would suggest otherwise: although cigarette smoke may be able to inhibit disease development, it may have deleterious effects on disease severity or prognosis (6, 16). By understanding the precise immunomodulating effects of cigarette smoke and/or its components, we may be able to use this information to halt or reverse granulomatous inflammation once started with analogs of nicotine or other components of cigarette smoke. Hopefully these issues will be explored further in this or other relevant animal models and human studies to help us better understand how to inhibit granulomatous lung diseases. Until we gain more information, we cannot be ambiguous about our recommendations for smoking cessation to our patients.

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