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.
|1.||Ezzati M, Lopez AD. Estimates of global mortality attributable to smoking in 2000. Lancet 2003;362:847–852.|
|2.||Centers for Disease Control and Prevention. Cigarette smoking–attributable morbidity—United States, 2000. MMWR 2003;52:842–844.|
|3.||Sopori M. Effects of cigarette smoke on the immune system. Nat Rev Immunol 2002;2:372–377.|
|4.||Blanchet M, Israël-Assayag E, Cormier Y. Inhibitory effect of nicotine on experimental hypersensitivity pneumonitis in vivo and in vitro. Am J Respir Crit Care Med 2004;169:903–909.|
|5.||Warren C. Extrinsic allergic alveolitis: A disease commoner in nonsmokers. Thorax 1977;32:567–573.|
|6.||Ohtsuka Y, Munakata M, Tanimura K, Ukita H, Kusaka H, Masaki Y, Doi I, Ohe M, Amishima M, Homma Y, et al. Smoking promotes insidious and chronic farmer's lung disease, and deteriorates the clinical outcome. Intern Med 1995;34:966–971.|
|7.||Douglas JG, Middleton WG, Gaddie J, Petrie GR, Choo-Kang YF, Prescott RJ, Crompton GK. Sarcoidosis: a disorder commoner in non-smokers? Thorax 1986;41:787–791.|
|8.||Newman L, Bresnitz EA, Rose C, Rossman M, Terrin ML, Barnard J, and the ACCESS Group. Environmental and occupational factors associated with sarcoidosis risk: A case control etiologic study of sarcoidosis. Am J Respir Crit Care Med 2001;163(5):A959.|
|9.||Baldwin CI, Todd A, Bourke S, Allen A, Calvert JE. Pigeon fanciers' lung: effects of smoking on serum and salivary antibody responses to pigeon antigens. Clin Exp Immunol 1998;113:166–172.|
|10.||Robbins CS, Dawe DE, Goncharova SI, Pouladi MA, Drannik AG, Swirski FK, Cox G, Stampfli MR. Cigarette smoke decreases pulmonary dendritic cells and impacts antiviral immune responsiveness. Am J Respir Cell Mol Biol 2004;30:202–211.|
|11.||Valeyre D, Soler P, Clerici C, Pré J, Battesti J-P, Georges R, Hance AJ. Smoking and pulmonary sarcoidosis: effect of cigarette smoking on prevalence, clinical manifestations, alveolitis, and evolution of the disease. Thorax 1988;43:516–524.|
|12.||Nouri-Shirazi M, Guinet E. Evidence for the immunosuppressive role of nicotine on human dendritic cell functions. Immunology 2003;109:365–373.|
|13.||McCue JM, Link KL, Eaton SS, Freed BM. Exposure to cigarette tar inhibits ribonucleotide reductase and blocks lymphocyte proliferation. J Immunol 2000;165:6771–6775.|
|14.||Matsunaga K, Klein TW, Friedman H, Yamamoto Y. Involvement of nicotinic acetylcholine receptors in suppression of antimicrobial activity and cytokine responses of alveolar macrophages to Legionella pneumophila infection by nicotine. J Immunol 2001;167:6518–6524.|
|15.||Ouyang Y, Virasch N, Hao P, Aubrey MT, Mukerjee N, Bierer BE, Freed BM. Suppression of human IL-1beta, IL-2, IFN-gamma, and TNF-alpha production by cigarette smoke extracts. J Allergy Clin Immunol 2000;106:280–287.|
|16.||Strom KE, Eklund AG. Smoking does not prevent the onset of respiratory failure in sarcoidosis. Sarcoidosis 1993;10:26–28.|