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The Proceedings of the American Thoracic Society 6:596-601 (2009)
© 2009 The American Thoracic Society
doi: 10.1513/pats.200904-017RM
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Senescence Hypothesis for the Pathogenetic Mechanism of Chronic Obstructive Pulmonary Disease

Kazutetsu Aoshiba1,2 and Atsushi Nagai2

1 Pulmonary Division, Graduate School of Medical Science, and 2 First Department of Medicine, Tokyo Women's Medical University, Tokyo, Japan

Correspondence and requests for reprints should be addressed to Kazutetsu Aoshiba, M.D., First Department of Medicine, Tokyo Women's Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: kaoshiba{at}chi.twmu.ac.jp

ABSTRACT

We report herein that pulmonary emphysematous lesions appear to be a dynamic phenomenon that involves not only the gradual loss of alveolar structure but also apoptosis, cellular proliferation, and cellular senescence. Cellular proliferation compensates for increased alveolar cell apoptosis in patients with chronic obstructive pulmonary disease (COPD). However, smoking, age, and the increased cell cycle turnover that compensates for apoptosis accelerate alveolar cell senescence, thereby halting cellular proliferation and tipping the balance toward apoptosis, which, in turn, promotes the formation of emphysematous lesions. As a result, alveolar cells disappear and the emphysematous lesions progress. At the same time, cellular senescence is believed to induce inflammation. More specifically, senescent alveolar cells induce inflammation by producing various inflammatory cytokines in tissue. Lymphocytes and Clara cells may also age more rapidly in the lungs of patients with COPD. Lymphocyte senescence may induce an autoimmune reaction and increase susceptibility to infection, and Clara cell senescence may impair airway regeneration as well as sustain airway inflammation. Thus, cellular senescence may be involved in arrested tissue repair, chronic inflammation, and increased susceptibility to infection, which are the typical features of COPD.

Key Words: chronic obstructive pulmonary disease • apoptosis • cellular proliferation • cellular senescence • telomere

The incidence of chronic obstructive pulmonary disease (COPD) increases with age (1). Older people are exposed to cigarette smoke for longer periods, and age itself is a factor in the etiology of COPD. COPD occurs when those in the approximately 15% of the population who are sensitive to cigarette smoke reach a certain age. In this paper we report evidence suggesting that cellular senescence may be involved in the pathogenesis of COPD.

APOPTOSIS IN PULMONARY EMPHYSEMA

Histopathological analysis for the lungs in pulmonary emphysema, a major form of COPD, has shown that alveolar structures have been destroyed and lost, resulting in enlarged air spaces. For approximately 40 years the etiology of pulmonary emphysema has been explained in terms of a protease–antiprotease imbalance hypothesis, in which elastase produced by smoke-activated neutrophils and macrophages causes emphysematous lesions by destroying the extracellular matrix that makes up alveolar structures (2, 3). This hypothesizes that the initial lesion in pulmonary emphysema is a damaged extracellular matrix, and this hypothesis has been supported by many studies showing elevated expression of proteases and loss of extracellular matrix in emphysematous lungs in comparison with normal lungs (2, 3). However, this hypothesis does not fully explain why alveolar cells are lost in emphysema. An alternative hypothesis that has been tested for the last 5 to 6 years states that the loss of alveolar wall structures through epithelial and endothelial apoptosis is the cause of pulmonary emphysema (4–7). However, these hypotheses (i.e., the protease–antiprotease imbalance hypothesis and the apoptosis hypothesis) are complementary, not contradictory. We hypothesize that pulmonary emphysematous lesions, a major form of COPD, are a dynamic phenomenon involving not only damage to the extracellular matrix but also apoptosis, cellular proliferation, and senescence.

First, we investigated whether apoptosis is involved in the pathogenetic mechanism of pulmonary emphysema (5). We detected apoptosis in lung tissue by terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) and immunohistochemistry for Bax, a proapoptotic protein. TUNEL-positive cells and Bax-positive cells were seen in the alveolar walls of patients with pulmonary emphysema, and double staining revealed that many of them were epithelial membrane antigen– and surfactant protein-A–positive type II alveolar epithelial cells. Semiquantitative analysis showed that the number of TUNEL-positive cells in patients with pulmonary emphysema was significantly higher than in control smokers and nonsmokers. Our findings corroborated those of other investigators showing increased levels of alveolar epithelial and/or endothelial apoptosis in the lungs of patients with emphysema (6, 7). However, because these findings did not prove that an increase in apoptosis causes pulmonary emphysema, we conducted an animal study to determine whether apoptosis causes pulmonary emphysema (8). We introduced activated caspase 3, which induces apoptosis, into alveolar cells in the lungs of mice by using the protein transfection reagent Chariot (Active Motif, Carlsbad, CA). The enzyme destroyed the alveolar walls, and emphysematous lesions with enlarged air spaces formed as a result. When Asp-Glu-Val-Asp, a specific inhibitor of caspase 3, was injected concurrently, progression of the emphysematous lesions was suppressed. Moreover, injecting nodularin, which activates caspase 3, into the trachea induced emphysematous lesions in mice, suggesting that alveolar cell apoptosis causes pulmonary emphysema.

COMPENSATORY MECHANISM FOR APOPTOSIS IN PULMONARY EMPHYSEMA

We found that the median proportion of TUNEL-positive alveolar epithelial cells in the lungs of patients with emphysema was approximately 0.4% (5). The TUNEL-positive cells should disappear the next day, and we assume that if 0.4% of the cells in the lungs are lost every day, the number of cells remaining at the end of 365 days should be 23.2% of the original number according to an equation of (1 – 0.004)365 = 0.996365 = 0.232. However, pulmonary emphysema is a disease that gradually progresses over decades, suggesting the existence of a compensatory mechanism for apoptosis.

We therefore investigated cellular proliferation in the lungs of patients with pulmonary emphysema (5). Proliferating cell nuclear antigen (PCNA) and topoisomerase II{alpha}, which are often used as cell proliferation markers, were used to compare cellular proliferation in the lungs of patients with emphysema, control smokers, and nonsmokers. The results showed that the proportion of proliferating alveolar cells in the patients with pulmonary emphysema was significantly higher. In other words, cellular proliferation appears to compensate for apoptosis.

Thus, we speculate that pulmonary emphysematous lesions are a dynamic phenomenon that involves not only the gradual loss of alveolar structure but also apoptosis and compensatory cellular proliferation.

APOPTOSIS–PROLIFERATION IMBALANCE IN PULMONARY EMPHYSEMA

It is also known, however, that the cells lost as a result of apoptosis in severe pulmonary emphysema are not all replaced by cellular proliferation. Calabrese and colleagues proposed an apoptosis–proliferation imbalance hypothesis that states that cellular proliferation does not increase at the same rates as apoptosis in severe pulmonary emphysema, and the excess of apoptosis causes the loss of alveolar cells that results in the formation of emphysematous lesions (9). Imai and colleagues showed that apoptosis and proliferation do not increase at the same rate (7). They found a significant inverse correlation between the lung surface area and apoptosis, but no correlation between the lung surface area and cellular proliferation, suggesting that although both apoptosis and proliferation increase during emphysema, apoptosis in excess of proliferation contributes to the formation of emphysema (7). Their findings suggest that the rate of cellular proliferation in emphysematous lungs is insufficient to replace apoptotic cells.

We speculate that cellular senescence is the cause of the insufficient cellular proliferation in pulmonary emphysema. Cellular senescence is defined as a state in which cellular proliferation is impossible, even when proliferation is stimulated, and it is different from cellular differentiation (10). Two possible mechanisms of cellular senescence are replicative senescence and stress-induced premature senescence (11, 12).

CIGARETTE SMOKE INDUCES CELLULAR SENESCENCE

Because oxidative stress is common in the lungs, and smoking is a common inducer of oxidative stress, we investigated the effects of smoking on cellular senescence (13). Figure 1 shows the results of an in vitro experiment conducted on alveolar type II epithelium-like A549 cells, which were exposed to cigarette smoke extracts (13). The results showed that the levels of senescence-associated β-galactosidase, a senescence-related marker, had increased, and that the cells exhibited senescent morphology (i.e., giant, flattened cells). Exposure to smoke also resulted in changes indicative of cellular senescence, including lysosome hypertrophy, reduced BrdU uptake, and elevated p21CIP1/WAF1/Sdi1 protein. These changes were also seen in the lungs of mice exposed to cigarette smoke. Exposing mice to cigarette smoke for 3 weeks resulted in an increase in senescence-associated β-galactosidase level in type II alveolar epithelial cells and caused lipofuscin accumulation, indicating that stress-induced premature senescence, rather than replicative senescence, had occurred (13).


Figure 1
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  		Figure 1. Senescent phenotype of A549 cells exposed to cigarette smoke extracts (CSE). (B, D, and F) A549 cells were exposed, or (A, C, and E) were not exposed to CSE solution (0.01 vol/vol %) for 36 hours and examined for markers of cellular senescence. (A and B) Staining for SA β-galactosidase activity (original magnification, x200). (C and D) Cell morphology, characterized by flat, enlarged cells, after exposure to CSE (D) (x200). (E and F) Lysosome staining with acridine orange shows a marked increase in the number and size of the lysosomes (orange fluorescence) in cells after treatment with CSE (F) (x200). The green fluorescence is emitted by the binding of acridine orange to nucleic acids. (G) Incorporation of BrdU by A549 cells. **P < 0.01 versus control cells not treated with CSE. All data are the means ± SEM of the results for four samples. Reprinted by permission from Reference 13.

 
CELLULAR SENESCENCE IN PATIENTS WITH PULMONARY EMPHYSEMA

Next, we measured cellular senescence makers in human emphysematous lungs. Proteins p16INK4a and p21CIP1/WAF1/Sdi1 antagonize cyclin-dependent kinase, which is required for cell cycle turnover, and they are used as senescence markers. We investigated the expression of p16INK4a and p21CIP1/WAF1/Sdi1 proteins in type II alveolar cells (14).

The number of surfactant protein-A–positive type II alveolar epithelial cells expressing senescence markers was higher in the patients with pulmonary emphysema than in control smokers and nonsmokers, and these findings were also seen in CD31-positive vascular endothelial cells (Figure 2) (14). Expression of the senescence-related markers p16INK4a and p21CIP1/WAF1/Sdi1 is high in pulmonary emphysema. When fluorescence in situ hybridization was used to measure telomere length, the telomere length of the patients with pulmonary emphysema was found to be shorter than that of nonsmokers (Figure 3), confirming that the alveolar cells of patients with pulmonary emphysema are senescent (14).


Figure 2
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  		Figure 2. Levels of p16INK4a and p21CIP1/WAF1/Sdi1 expression and lipofuscin accumulation in alveolar cells. The horizontal bars indicate the median values. NS = not significant. Reprinted by permission from Reference 14.

 

Figure 3
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  		Figure 3. Quantitative analysis of telomeres in (A) alveolar type II cells, and (B) endothelial cells. The horizontal bars indicate the median values. NS = not significant. Reprinted by permission from Reference 14.

 
RELATIONSHIP BETWEEN PULMONARY EMPHYSEMATOUS LESIONS AND SENESCENCE

Because cellular proliferation should stop when alveolar cells reach the senescent stage (10), we examined the relationship between proliferation and senescence in PCNA-positive type II alveolar epithelial cells and CD31-positive vascular endothelial cells (14). An inverse correlation was found between p16INK4a expression and PCNA expression in alveolar epithelial cells and vascular endothelial cells, indicating that alveolar cell senescence is associated with a decrease in cellular proliferation and regeneration. FEV1 was also correlated inversely with the numbers of p16INK4a-positive type II alveolar epithelial cells and vascular endothelial cells, and as cellular senescence progressed, the pulmonary emphysema became more severe.

We hypothesize that smoking causes alveolar cell apoptosis even in young people, but that it is compensated for by cellular proliferation, and no emphysematous lesions are produced. In contrast, in elderly patients with pulmonary emphysema, cellular senescence is accelerated as a result of cigarette smoke exposure for longer periods and increased cell cycle turnover compensating for alveolar cell apoptosis. The aging process is also involved in accelerating the senescence of alveolar cells. When cellular senescence occurs, cellular proliferation is lost, and the balance is tipped toward apoptosis and the formation of pulmonary emphysematous lesions (Figure 4). This hypothesis may explain why older people are prone to develop emphysema, but does not explain why only some smokers develop emphysema.


Figure 4
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  		Figure 4. Apoptosis–proliferation imbalance induced by cellular senescence in patients with chronic obstructive pulmonary disease.

 
As for the mechanisms of cellular senescence, smoking causes apoptosis, and compensatory increase in cell cycle turnover shortens telomere length and ages cells. In addition, oxidative stress causes cellular senescence via a stress-dependent mechanism (stress-induced premature senescence). Moreover, in the elderly, cell cycle turnover is increased, and smoking reduces the already shortened telomere length, which accelerates cellular senescence and stops cellular proliferation. As a result, alveolar cells disappear and emphysematous lesions progresses. However, cellular senescence appears to have another role.

RELATIONSHIP BETWEEN CELLULAR SENESCENCE AND INFLAMMATION

Aging is closely related to inflammation, leading to combination of inflammation and aging in the term "inflamm-aging" (15). Inflamm-aging is believed to be the result of the lifelong antigenic burden and exposure to damaging insults (15). However, recent evidence suggests a close relationship between cellular senescence and inflammation. For example, recent studies have shown that senescent cells produce various inflammatory cytokines, thereby causing inflammation (16–18).

When A549 cells were aged by the addition of a telomerase inhibitor, the levels of inflammatory cytokines, including tumor necrosis factor (TNF)-{alpha}, IL-6, and IL-8, in the supernatant increased (19), and when stimulated with LPS, their levels increased further. Similarly, nuclear factor-{kappa}B, the master transcription regulator of inflammation, has also been found to be activated in senescent cells. Senescent alveolar cells may induce inflammation in the surrounding tissue.

We analyzed gene expression in the lungs of old mice (24 mo) and young mice (3 mo) by using cDNA arrays. The results showed that expression of nine genes was up-regulated in old mice and that eight of the nine genes were proinflammatory genes (20), whereas none of the five genes with reduced expression were related to inflammation. The number of inflammatory cells around vessels, airways, and alveoli was then counted in old mice and young mice. The numbers of CD8-positive and B cells around the alveoli of the old mice were 2.1-fold and 2.8-fold higher, respectively. The numbers of B cells and macrophages were higher around airway tracts, and the numbers of CD4/8-positive cells and B cells were higher around vessels, confirming that inflammation in the lungs of mice increases with age (20).

We used human lung tissue to determine whether similar phenomena occur in humans. Expression of phosphorylated I{kappa}B and TNF-{alpha} was found to be increased in p16INK4a-positive type II epithelial cells, suggesting that senescent alveolar cells promote inflammation at the cellular level (19). Furthermore, plotting the data of individual patients revealed a positive correlation between the degree of p16INK4a-positive cell senescence and the severity of inflammation in patients with emphysema. Inflammatory reactions occurred in senescent alveolar areas.

Based on the above findings, we speculate that smoking and age cause cellular senescence and cause cellular proliferation to stop. When tissue regeneration is blocked, the number of alveolar cells decreases, and the formation of emphysematous lesions progresses. At the same time, cellular senescence is believed to be involved in inflammation. Inflammation causes inflammatory cells to produce proteases, and the protease–antiprotease imbalance causes pulmonary emphysema to progress.

We deduced that inflammatory cells also age in patients with COPD. A study of 80 subjects by Morlá and colleagues that used peripheral blood lymphocytes to investigate senescence and telomere length in smokers and nonsmokers found an inverse correlation between the amount of smoking and telomere length (21), and the same results were obtained in a study involving 1,000 subjects. Valdes and colleagues measured the telomere length of lymphocytes from 1,112 healthy women and found that telomere length was shorter in the smokers, and that smoking 10 cigarettes a day for 40 years aged lymphocytes by 7.4 years (22). Savale and coworkers, on the other hand, studied 136 patients with COPD, 113 smokers, and 42 nonsmokers, and found that telomere length in lymphocytes was shorter in the patients with COPD and that there was no relationship between telomere length and tobacco exposure in the patients or control subjects (23). These findings suggest that lymphocytes in the circulating blood of patients with COPD are senescent. However, whether lymphocytes in the lungs of patients with COPD are also senescent is unclear.

Two potential changes are associated with lymphocyte senescence (24). First, T-cell dysfunction lowers cellular immunity, which increases susceptibility to infection; second, lymphocyte senescence induces an autoimmune reaction (24). In fact, growing evidence suggests that senescent T cells are cytotoxic and induce chronic inflammation (25). For example, cellular senescence has been reported to be involved in loss of T-cell regulation and control of autoreactivity and tissue injury, leading to an autoimmune inflammation (26). Autoimmunity is thought to be involved in the mechanism of chronic inflammation in COPD (27), and patients with COPD have been shown to have an increased number of circulating senescent T cells expressing an autoimmune phenotype with loss of CD28 and increased production of IFN-{gamma}, perforin, and granzyme B (28). Thus, lymphocyte senescence in patients with COPD may be involved in persistent infection and chronic inflammation, which are the pathogenic features of COPD.

AIRWAY SENESCENCE IN COPD

The airway lesions in COPD may be associated with senescence of Clara cells, which are progenitor cells of the peripheral airway epithelium. In our study the number of Clara cells with senescence markers was found to be higher in patients with COPD than in control nonsmokers, suggesting that cellular senescence is also involved in the airway lesions associated with COPD (unpublished data). We later attempted to prepare a murine model of senescent Clara cells.

Naphthalene specifically destroys Clara cells, and when injected into the abdominal cavity of mice, the Clara cells were decimated. However, because of their great proliferative potential, the Clara cells regained their original numbers in about 1 week. When BrdU was injected after naphthalene injury, it was absorbed into the DNA of remaining Clara cells, and the cells that absorbed BrdU eventually became senescent (29). When naphthalene injections and BrdU injections were repeated for 1 month during the cellular proliferation process, the number of Clara cells remained low, and few bronchiolar epithelial cells were regenerated (30). The remaining Clara cells were found to overexpress phosphorylated p38-MAPK and senescence-associated β-galactosidase. When the lung tissue was stained for CD45, a leukocyte marker, leukocytes were found to have aggregated around the airway of mice with senescent Clara cells. These findings suggested that airway cell senescence is linked to inflammation.

CELLULAR SENESCENCE AND COPD

In summary, smoking and aging cause alveolar and airway cells to senesce (Figure 5). Senescence stops tissue repair and at the same time causes chronic inflammation. If lymphocyte senescence also occurred in the lung, it would contribute to chronic inflammation and increased susceptibility to infection (Figure 5). Arrested tissue repair, chronic inflammation, and increased susceptibility to infection are the typical features of COPD.


Figure 5
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  		Figure 5. Senescence hypothesis for the pathogenetic mechanism of chronic obstructive pulmonary disease.

 
Our COPD senescence hypothesis may be able to answer the following three questions: (1) Why does COPD become more severe with age? (2) Why does COPD progress gradually? and (3) Why does COPD progress, even after cessation of smoking?

The existing hypothesis for the pathogenetic mechanism of COPD is explained in terms of proteases, oxidants, and inflammation, whereas our hypothesis is explained in terms of apoptosis, proliferation, and senescence (Figure 6). We believe that the two hypotheses can be integrated into a single hypothesis by linking senescence and inflammation (Figure 6).


Figure 6
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  		Figure 6. Integration of the two hypotheses.

 
We believe future studies are needed to determine (1) which is the dominant driving force of emphysema, replicative senescence or stress-induced premature senescence, or both, and (2) whether the senescence hypothesis holds for patients with COPD who do not smoke.

ACKNOWLEDGMENTS

The authors thank their collaborators, Drs. Naoko Yokohori, Takao Tsuji, Shigemitsu Onizawa, and Zhou Fang.

FOOTNOTES

Supported by Grant-in-Aid for Scientific Research #19590917 from the Ministry of Education, Science, and Culture, Japan, and by the Ministry of Health, Labor, and Welfare of Japan to investigate intractable diseases.

Conflict of Interest Statement: K.A. received $10,001 to $50,000 in grant support from the Japanese government. A.N. received $10,001 to $50,000 in grant support from the Japanese government.

(Received in original form April 8, 2009; accepted in final form August 12, 2009)

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