© 2007 American Thoracic Society doi: 10.1164/rccm.200612-1800ED
"In the Beginning" of COPDIs Evolution Important?University of Crete Medical School, Crete, Greece Chronic obstructive pulmonary disease (COPD) is a major health problem worldwide, with increasing prevalence, morbidity, and mortality (1, 2). Although COPD is a very common disease and the primary cause, chronic cigarette smoking, has been identified, its pathogenesis is poorly understood. In addition, the epidemiologic observation that only a fraction of smokers develop clinically relevant COPD remains unexplained. COPD is the result of environmental insult and host reaction, most probably genetically predetermined (1, 2). Recent guidelines emphasize that COPD is characterized by progressive, not fully reversible airflow limitation, a result of an abnormal inflammatory reaction of the lungs to inhaled noxious gases and particles (1, 2). A number of observational studies have shown that immune cells, such as alveolar macrophages, polymorphonuclear neutrophils, and T and B lymphocytes, are increased in COPD (3). An autoimmune component has been proposed to contribute to the development of COPD (4). In particular, CD8+ cytotoxic T cells have been shown to be increased in COPD (5–7). Dendritic and epithelial cells may also contribute to the pathogenesis of COPD (8, 9). The interaction, communication, and recruitment of these cell populations are modulated by altered expression of various cytokines, chemokines, and adhesion molecules (10). Although the pathology of central and peripheral small airways, lung parenchyma, and pulmonary vessels has been extensively studied in COPD, the beginning of this "burning fire" and its perpetuation (abnormal inflammation persists even after smoking cessation) is not fully understood. The article by Vernooy and coworkers in this issue of the Journal (pp. 464–472) provides an investigation of the protein and mRNA expression of granzyme A (Gr A) and B (Gr B) in lung tissue of patients with COPD and reports the involvement of type II pneumocytes in the pathogenesis of the disease (11). The authors found Gr A and Gr B in CD8+ T cells, CD57+ natural killer cells, type II pneumocytes, and alveolar macrophages. However, epithelial cells stained positively only for Gr A, and type II cells showed significantly higher Gr A expression in severe COPD (11). These novel findings provide new insights into the interaction between the barrier cells (bronchial epithelial cells and pneumocytes) and the immune system. The above findings are complementary to those reported by Chrysofakis and colleagues that showed CD8+ T cells from patients with COPD produce more perforin and are extremely cytotoxic (12). Because it is known that granzymes and perforin are the basic armature of the defense cells (CD8+) that induce apoptosis in targeted cells, the above findings may add valuable information concerning the beginning of the abnormal inflammatory cascade in COPD (11). A hypothesis involving the pathogenesis of COPD could be that the immune system responds to cigarette smoke the same way as to a viral infection. For millions of years, the defense mechanism of the respiratory system underwent evolutionary maturation to protect the host from viral and bacterial infections. Smoking or other noxious agents are novel insults in the history of mankind (only 500 yr) and, thus, the immune system may react to cigarette smoke in a similar way to the responses induced for millions of years to viral or bacterial infections, and predominately characterized as a type I immune response. In the initial stages of COPD, cigarette smoking affects the air–lung barrier system and, in particular, its cellular component via repeated oxidative insults. Oxidative stress damages the DNA of lung cells, probably at the microsatellite level, leading to acquired mutations. These mutations, expressed as microsatellite instability, permanently alter DNA auto-repair ability (13). As a result, membrane proteins may be altered and recognized as foreign by dendritic cells. Dendritic cells travel to the draining lymph nodes with this new signal as a result of altered membrane proteins where they then present it to naive T lymphocytes, inducing proliferation predominately of CD8+ cytotoxic type I T lymphocytes (Tc1) (14). These T cells migrate to the sites of the initial insult performing cytotoxic functions. Thus, the immune system is misled, interpreting the information caused by smoking as a "viral" insult, and turning the CD8+ T cells with their release of perforin and granzymes against epithelial cells. Perforin polymerizes to form pores in the target cells' membranes, while granzymes, as serine proteases, enter the cytoplasm of the target cells, activating apoptosis or altering their function (11, 12). The results of Vernooy and colleagues that are reported in this issue of the AJRCCM (11) support this autoimmune hypothesis because of the increased staining of GrA in type II cells. Furthermore, these findings are in agreement with those reported by Vlachaki and coworkers who demonstrated altered production of surfactant protein A by type II pneumocytes from patients with COPD (15). Obviously, the above hypothesis, which implicates evolutionary responses to viral infections, needs further experimental exploration. However, it is an attractive scenario to describe the "beginning" of the abnormal inflammation in COPD, prior to lung tissue destruction and remodeling. The coexistence of viral infection and smoking could be an alternative process, although the results of Vernooy and coworkers' study (11) did not support this hypothesis. However, latent adenoviral infection as proposed by Retamales and colleagues (16) was not excluded. More research is needed to verify the role of perforin and granzymes in the pathogenesis of COPD. Investigations should focus on the interaction between barrier cells (bronchial cells, epithelial cells, and pneumocytes) and immune cells (dendritic cells and T lymphocytes) to clarify the beginning of the "burning" process of COPD. FOOTNOTES Conflict of Interest Statement: S.N. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. REFERENCES
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