© 2002 American Thoracic Society
p21CIP1/WAF1 and the Immunologic Fate of Macrophages in SmokersAt the Crossroad between Proliferation, Survival, and DeathIstituto di Medicina Generale e Pneumologia Cattedra di Malattie Respiratorie University of Palermo and IFR-CNR Palermo, Italy Apoptosis is generally defined as a genetic program that controls tissue homeostasis and eliminates unneeded, senescent, or damaged cells without eliciting an inflammatory response. With fascination, we have learned that apoptosis involves intertwined gene families of factors capable of stimulating or inhibiting cell death and that its deregulation may be critical in the pathogenesis of human diseases (1). Compelling evidence suggests that apoptosis is a central regulatory checkpoint, which limits the intensity of immune responses that might otherwise prove debilitating. When this checkpoint is altered and immune, somatic or myeloid cells elude apoptosis, diseases as diverse as autoimmune disorders, cancers, or inflammatory diseases may result (2–4). The link between apoptosis dysregulation and airway inflammation has raised great interest mainly because of its effects on the immunologic fate of cells that, recruited from the bloodstream, reach the inflamed airways. A general hypothesis is that inhibition or delayed apoptosis of inflammatory cells contributes to "tissue load" of the cells (2). In asthma, the delayed eosinophil apoptosis in the bronchial mucosa has been indicated as a novel mechanism by which eosinophils specifically accumulate in the airways (4), suggesting that the control of the "longevity" of inflammatory cells is a key step in the chronic evolution of an inflammatory process. In this issue of AJRCCM (pp. 724–731), Tomita and coworkers (5) tested the hypothesis that an imbalance between recruitment, proliferation, and apoptosis of airway macrophages may sustain the abnormal accumulation of these cells in the airways of smokers (6). By assessing the expression of the CC chemokine receptor CCR2 and of the proliferating cell nuclear antigen, Tomita and coworkers studied, respectively, the recruitment and proliferation of airway macrophages isolated from normal, healthy smokers and subjects with asthma. To explore whether the increased number of airway macrophages in smokers may result from their enhanced proliferation and/or survival, they also evaluated the expression of molecules regulating the cell cycle and apoptosis, such as p21CIP1/WAF1, p27, p53, Bcl-2, and Bcl-xL. The results clearly show that the increased number of airway macrophages in smokers is not due to an increased recruitment. It is marginally influenced by an enhanced proliferation but is mainly dependent on a reduced airway macrophage apoptosis. This important concept is supported by several findings. First, Tomita and coworkers found that Bcl-xL expression was higher in airway macrophages isolated from smokers than in normal and steroid-naive subjects with asthma. Bcl-xL belongs to the Bcl-2 family, which functions as cell death suppressors (7). Thus, an increased expression of Bcl-xL, in the absence of significant changes of p53 expression (7), supports the hypothesis that airway macrophages of smokers have a reduced propensity to undergo apoptosis and, as such, to accumulate in the airways.
Second, Tomita and colleagues found an increased p21CIP1/WAF1 expression in the airway macrophages of smokers with a prevalent cytoplasmic localization. p21CIP1/WAF1 inhibits cell cycle progression by binding to both G1 cyclin-dependent kinase complexes and to the proliferating cell nuclear antigen, preventing its subsequent ability to activate DNA polymerase These results highlight that apoptosis and proliferation are tightly coupled phenomena and that cell cycle regulators can ultimately influence both cell division and death. This apparent paradox is also demonstrated by the in vitro data generated by Tomita and coworkers (5), showing that an increased cytoplasmic p21CIP1/WAF1 expression enhances the survival of cultured bronchial epithelial cells against oxidative stress (H2O2) and promotes transition from the G1 to the G2/M phase of the cell cycle. A possible interpretation of these results is that oxidative stress induced by cigarette smoke can lead to an imbalance between apoptosis and proliferation of epithelial cells. The histologic correlate of this imbalance may be the development of squamous cell metaplasia of the epithelium of smokers and patients with chronic obstructive pulmonary disease and, potentially, an enhanced epithelial transitions from normal to hyperplastic to dysplastic to carcinomatous. It is indeed likely that the prolongation of the cell life span together with an increased proliferation augments the risk for epithelial cells to acquire oncogenic changes, such as chromosomal abnormality and viral infection, resulting in malignant transformation or overt tumor progression. Thus, the complexity of these dynamic cellular and molecular mechanisms raises a number of key questions that still remain unanswered. The first question deals with the mechanisms involved in monocyte–macrophage recruitment. In addition to CCR2, other chemokine receptors might be responsible for the migration of blood monocytes. In addition, although CCR2 is the receptor for monocyte chemotactic protein (MCP)-1, like most chemokine receptors, CCR2 is activated by multiple agonists, including MCP-3, MCP-4, and MCP-5. The multiplicity of receptor usage suggests that chemokines may have redundant functions in vivo and may contribute to an amplification of the monocyte recruitment and differentiation in the lung (9). Thus, the mechanisms underlying monocyte migration and differentiation need to be investigated further to obtain a greater understanding of their real contribution to the increased number of airway macrophages in the airways of smokers. The second question is, "Why, in airway macrophages of smokers, does p21CIP1/WAF1 translocate in the cytoplasm, and what is the mechanism involved? Tomita and coworkers conclude that this is not due to caspase cleavage and suggest that Ciz1, a novel p21CIP1/WAF1-interacting protein, may regulate the cellular localization of p21 (5). However, they do not provide evidence supporting this hypothesis, and the potential effects of cigarette smoking or oxidants on Ciz1–p21CIP1/WAF1 interaction still have to be demonstrated. The last fascinating question deals with the possible link between inflammation and cancer and the subtle barrier separating these two processes. A substantial body of evidence indicates that the response of the body to a cancer is not a unique mechanism but has many parallels with inflammation and wound healing, suggesting a redundancy of genetic alterations in both inflammation and cancer (10). Inflammatory mediators contribute to neoplasia by inducing proneoplastic mutations, adaptive responses, resistance to apoptosis, and angiogenesis (10). These changes confer a survival advantage to a susceptible cell. Thus, the dysregulation of cell apoptosis and proliferation shown by Tomita and coworkers in airway cells of smokers have important implications not only for airway inflammation but also for tumorigenesis. A better understanding of the molecular links between these processes is a challenging task in respiratory research and may open new horizons in the prevention and treatment of chronic obstructive pulmonary disease and lung cancer. REFERENCES
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