Is Vitamin C Good For Copd

Is Vitamin C Good For Copd

Our results suggest that vitamin C not only prevents cigarette smoke–induced emphysema in senescence marker protein-30 knockout mice but also restores emphysematous lungs. Vitamin C treatment may provide a new therapeutic strategy for treating cigarette smoke–induced emphysema.

Pulmonary emphysema is a major component of chronic obstructive pulmonary disease (COPD), a major cause of morbidity and mortality worldwide. The most prevalent cause is chronic exposure to cigarette smoke and environmental pollutants (1). Cigarette smoke–triggered oxidative stress causes lung inflammation, apoptosis, protease/antiprotease imbalance, accelerated aging, and breakdown of the lung structure maintenance program (1, 2). However, despite the ubiquity of COPD, no specific cure or means of regenerating injured lung parenchyma has been available. Only cessation of cigarette smoking, bronchodilator therapy, and long-term oxygen supplementation improve survival rates of these patients (3).

Vitamin C (VC) is a potent antioxidant and plays an essential role in human health and diseases. Nevertheless, humans cannot synthesize VC, and they derive this vitamin only from dietary sources, whereas most animals, including mice, synthesize VC. Several epidemiologic studies indicate that VC provides a protective effect on lung function, which may become a modifier for the risk of smoke-induced lung injury (4–6).

Various animal models of smoke-induced or elastase-induced emphysema have been invented to explore the pathogenesis of COPD in humans. Results from several of these studies indicate that the prevention of smoke-induced emphysema and reversal of elastase-induced emphysema are achievable (7–11). We have established a reliable animal model of smoke-induced emphysema by generating senescence marker protein-30 knockout (SMP30-KO) mice, which have an inherent accelerated aging process (12). Under standard breeding conditions, SMP30-KO mice manifest a shorter-than-normal lifespan (13), during which they develop emphysema within 8 weeks of exposure to cigarette smoke due to excessive oxidative stress (8). With this model, we demonstrated that SMP30 is a gluconolactonase in L-ascorbic acid biosynthesis and that its genetic disruption results in a defect of VC synthesis similar to that in humans (12). A complete lack of dietary VC intake therefore impairs lung development and generates pulmonary emphysema, whereas insufficient VC level in the lungs under a standard dietary VC intake supports lung growth but results in a senile lung prematurely (8, 14, 15).

By taking experimental advantage of SMP30-KO mice in which the effect of VC on smoke-related lung pathology can be objectively evaluated, we tested whether smoke-induced emphysema persists after smoking cessation. In addition, we determined whether this experimental model of smoke-induced emphysema in mice could be used for developing an interventional strategy to restore lungs harmed by persistent smoke-induce emphysema. Here, we report that VC treatment effectively prevents cigarette smoke–induced emphysema in SMP30-KO mice and restores lung tissue damaged by prolonged cigarette smoking.

Materials and Methods

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Animals, Preparation, and Morphologic Evaluation of the Lungs

SMP30-KO mice were established and maintained as described previously (16). We performed two sets of experiments in which SMP30-KO mice were exposed to cigarette smoke: a preventive study (Figure 1A ) and a treatment study (Figure 1B ). The first of these experiments was the preventive treatment in which 4-month-old mice received minimal VC (0.0375 g/l) [VC(L)] or physiologically sufficient VC (1.5 g/l VC) [VC(S)] and were exposed to cigarette smoke or smoke-free air for 2 months. Pulmonary evaluations followed when the mice were 6 months of age (Figure 1A ). In the second set of experiments (the treatment study), all 3-month-old mice had free access to water containing 0.0375 g/l VC and exposure to cigarette smoke or smoke-free air from 4 to 6 months of age. Mice were exposed to fresh air only with VC treatment or without VC treatment until they were killed at 8 months of age (Figure 1B ).

The lungs were processed as described previously (10), and the total cell counts and cell populations in each bronchoalveolar lavage fluid (BALF) specimen were determined (10). Air space size was assessed by the determination of mean linear intercepts (MLI) (17), and the destructive index (DI) was calculated to evaluate destruction (18). Pressure–volume and lung compliance were assessed by using a computer-controlled small animal ventilator (Flexivent; SCIREQ, Montreal, PQ, Canada) (19).

Measurement of Total VC, Oxidative Stress, and Protein Concentration

Total VC levels in the lung homogenates and plasma were determined by using a HPLC-electrochemical detection method (20). Reactive oxygen species (ROS) and glutathione peroxidase (GSH-Px) activity in the lungs were determined as previously described (15). The protein concentration was determined by BCA protein assay (Pierce Biotechnology, Inc., Rockford, IL) using BSA as a standard.

Determination of Vascular Endothelial Growth Factor, TNF-α, and mRNA Transcripts of Collagen

Vascular endothelial growth factor (VEGF) and TNF-α in the lung homogenates and VEGF in the BALF were determined using a commercially available ELISA kit (Quantikine Mouse TNF-α or VEGF kit; R&D Systems, Minneapolis, MN) according to the manufacturer's instructions, and the values were normalized by protein concentration. Amounts of mRNA transcripts of collagen І (Col1α2) and IV (Col4α1) in the lungs were determined as previously described (15).

Evaluation of Apoptosis and Cell Proliferation in the Lungs

Apoptosis and proliferation of lung cells were examined with immunohistochemistry using a rabbit polyclonal antibody against the ssDNA (Immuno-Biological Laboratories, Gunma, Japan) and Ki-67 (Novus Biologicals, Littleton, CO), respectively (10, 11). The percentage of apoptotic and proliferating cells (ratio of positively immunostained nuclei to total count of the nuclei present in the field) was determined as described previously (8, 10).

Statistical Analysis

Data are expressed as means ± SD. Statistical analysis was performed using one-way ANOVA followed by Tukey's post hoc test for multigroup comparisons. All statistical analyses were performed by using SPSS version 16.0 software (SPSS Inc., Chicago, IL). P < 0.05 was considered statistically significant.

Results

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Body Weights, Lung Inflammation, and Total VC Levels of SMP30-KO Mice

To investigate the effect of VC on growth and lung inflammation induced in mice by smoking, we measured changes in body weights, TNF-α level in the lungs, and cell number and population in BALF and VC levels in the plasma and lungs of four animal groups (i.e., the treatment study). Body weights of mice among the four groups did not change significantly from 2 to 6 months of age when exposure to cigarette smoke for 8 weeks (4–6 mo of age) was completed, whereas the body weights of the VC(L)→(L) smoke group were significantly lower than those of the other three groups at 7 and 8 months of age (Figure 2A ). There was no significant difference in the amount of chow and water ingested in all groups during the experiment (data not shown). In VC(L)→(L) groups, smoking exposure resulted in an approximately 10-fold increase of TNF-α in the lungs, although their exposure to smoke had stopped for 2 months before they were killed at 8 months of age (Figure 2B ). VC treatment for 2 months after the cessation of cigarette smoke exposure markedly decreased TNF-α in the lungs (69.5% decrease as compared with that of the VC(L)→(L) smoke group). Chronic exposure to cigarette smoke increased total cell counts in BALF at 6 months of age, but subsequent cessation of exposure for 2 months normalized total cell counts in BALF (Table 1). No significant difference of cell populations in BALF was observed among any of the four groups at 6 or 8 months of age. VC treatment for 2 months (from 6 to 8 mo of age) in SMP30-KO mice restored plasma VC levels to that of age-matched wild-type mice (data not shown), and the prior exposure to cigarette smoke for 2 months from 4 to 6 months of age did not influence VC level in plasma (Figure 2C ). In contrast, VC levels in the smoke-exposed lungs were not restored completely with VC treatment for 2 months [VC(L)→(S) air vs. VC(L)→(S) smoke, 141.9 ± 10.0 vs. 117.6 ± 20.1 μg/g lung tissue] (Figure 2D ). Total VC levels in the lungs from the VC(L)→(L) air and the VC(L)→(L) smoke-exposed group remained at very low levels (10.5 ± 2.0 and 6.9 ± 1.7 μg/g lung tissue at 8 mo of age, respectively).

Table 1: Cell Populations in Bronchoalveolar Lavage Fluid
Treatment Total cell count (×105) % Macrophages % Lymphocytes % Neutrophils
VC(L)
 Air 1.2 ± 0.3* 92.4 ± 1.3 4.8 ± 1.0 1.5 ± 0.6
 Smoking 1.8 ± 0.3 † 93.5 ± 2.0 4.5 ± 1.3 1.8 ± 0.5
VC(S)
 Air 1.0 ± 0.1 92.8 ± 1.9 5.3 ± 1.1 1.7 ± 0.9
 Smoking 1.4 ± 0.1 ‡ 94.5 ± 1.6 3.5 ± 0.6 1.8 ± 0.5
VC(L)→(L)
 Air 0.9 ± 0.1 93.1 ± 2.1 5.3 ± 1.4 1.7 ± 0.6
 Smoking 1.0 ± 0.1 94.5 ± 1.8 3.9 ± 1.1 1.5 ± 1.0
VC(L)→(S)
 Air 0.9 ± 0.1 92.4 ± 1.7 5.2 ± 0.9 1.9 ± 0.6
 Smoking 0.9 ± 0.1 93.3 ± 1.4 4.9 ± 1.0 1.6 ± 0.6

Mechanics and Morphometric Findings of the Lungs

We examined the mechanical properties of the lungs from SMP30-KO mice to assess the physiological consequences of chronic exposure to cigarette smoke from 4 to 6 months of age on the lungs of SMP30-KO mice (the preventive study). A statistically significant decrease in tissue elastance was demonstrated in the VC(L) smoke-exposed group as compared with the other three groups at 6 months of age (Figure 3A ), suggesting the development of cigarette smoke exposure–induced emphysema in this group of mice. In contrast, VC supplementation during the period of smoke exposure did not decrease lung tissue elastance.

We examined the lung specimens morphometrically to assess the effect of VC on lung damage induced by smoking in SMP30-KO mice. In the VC(L) group, cigarette smoke exposure for 2 months caused marked increases of MLI (VC(L) air vs. VC(L) smoke, 74.7 ± 2.1 vs. 96.8 ± 4.1 μm) (Figure 3B ). Similarly, the DI increased (VC(L) air vs. VC(L) smoke, 7.6 ± 0.6% vs. 15.7 ± 0.9%) (Figure 3C ) by 6 months of age. However, VC supplementation from 4 to 6 months of age prevented the increases of MLI and DI in the smoke-exposed group and maintained their levels comparable to those of the VC(L) air group at 6 months of age. After the establishment of smoke-induced emphysema at 6 months of age in the VC(L) smoke-exposed group, the smoke exposure ended, and those mice were treated with 1.5 g/l VC (VC(S)) or 0.0375 g/l VC (VC(L)) (the treatment study). VC treatment for 2 months after the cessation of cigarette smoke exposure restored MLI and DI to the same level as those of the VC(L)→(L) air group at 8 months of age, whereas the VC(L)→(L) smoke-exposed group at 8 months of age retained MLI and DI like those of the VC(L) smoke-exposed group at 6 months of age (Figures 3B and 3C ). The representative histological findings of lungs from each group at 8 months of age are shown in Figure 3D and support the contention that VC supplementation restored normalcy to morphometric variables in the VC(L)→(S) smoke-exposed group (Figure 3D , D) as compared with those in the VC(L)→(L) smoke-exposed group (Figures 3D , B). These results indicate that VC can prevent emphysema and can restore emphysematous lungs in SMP30-KO mice under our experimental conditions.

Effect of VC on Oxidative Stress and VEGF of the Lungs and BALF

To investigate the effect of VC on oxidative stress and disruption of the alveolar maintenance program induced by chronic smoke exposure, we measured ROS and GSH-Px activity in the lungs from each group at 6 or 8 months of age and measured VEGF in the lungs and BALF from each group at 8 months of age. GSH-Px is widely recognized as a main antioxidant defender of the lungs. In the VC(L) group, cigarette smoke exposure for 2 months resulted in an approximately 1.5-fold increase of ROS in the lungs at 6 months of age (Figure 4A ). VC supplementation for 2 months (from 4 to 6 mo of age) prevented ROS from increasing in the lungs due to smoke exposure. No significant difference in GSH-Px activity was detected among any groups at 6 or 8 months of age (Figure 4B ). When the VC(L)→(L) group was exposed to smoke from 4 to 6 months of age and subsequently treated with VC(L), their lungs showed an approximately 1.5-fold increase of ROS [VC(L)→(L) air vs. VC(L)→(L) smoke, 638 ± 202 vs. 960 ± 209 AU/min/mg protein] (Figure 4A ), and their BALF (and lungs) showed an approximately 0.5-fold decrease of VEGF [VC(L)→(L) air vs. VC(L)→(L) smoke, 170.1 ± 26.2 vs. 75.9 ± 11.5 pg/mg protein] (Figures 4C and 4D ) at 8 months of age, although the smoke exposure stopped for 2 months from 6 to 8 months of age. VC treatment from 6 to 8 months of age completely suppressed ROS production and restored VEGF in BALF and the lungs to the same level as that of the VC(L)→(L) air group. These results suggest that VC treatment after the cessation of cigarette smoke exposure suppressed oxidative stress and restored alveolar maintenance programs in the lungs of SMP30-KO mice.

Effect of VC on Collagen Synthesis in the Lungs

We previously reported that VC plays an important role in collagen synthesis in the lungs of SMP30-KO mice and that VC depletion causes major damage to lung parenchyma due to a decrease of collagen (15). To assess whether VC treatment affects collagen synthesis in lungs injured by chronic smoke exposure, we measured collagens I (Col1α2) and IV (Col4α1) mRNA in the lungs from each group at 8 months of age. Type I collagen is necessary for maintenance of pulmonary structure (21), and type IV collagen is a major component of basement membrane that has been implicated in the regulation of angiogenesis (22). VC treatment from 6 to 8 months of age caused more than 2-fold increases of collagen I and IV mRNA as compared with the corresponding VC(L)→(L) group (Figures 5A and 5B ), whereas smoking did not influence collagen synthesis in either the VC(L)→(L) or the VC(L)→(S) group. Thus, VC treatment appeared to improve the metabolism of extracellular matrix (ECM) proteins and angiogenesis of the lungs.

Effect of VC on Cellular Apoptosis and Proliferation in the Lungs

To investigate the mechanisms underlying the restoration of lung parenchyma by VC treatment, we analyzed cellular apoptosis and proliferation of the lung cells from 8-month-old SMP30-KO mice. Apoptosis and cell proliferation of the lung cells were examined with immunohistochemistry to discern their respective markers, single-stranded DNA (ssDNA) and Ki-67. In the VC(L)→(L) group, chronic smoke exposure resulted in an approximately 1.7-fold increase of the ratio of ssDNA-positive alveolar septal cells, although the smoke exposure ended 2 months before death: (VC(L)→(L) air vs. VC(L)→(L) smoke, 9.2 ± 1.9% vs. 15.7 ± 2.3%) (Figure 6A ). In contrast, VC treatment from 6 to 8 months of age significantly decreased the ratio of ssDNA-positive alveolar septal cells to the same level as that of VC(L)→(L) air group. Furthermore, VC treatment significantly increased the ratio of Ki67-positive alveolar septal cells, whereas smoke exposure significantly decreased the ratio of Ki67-positive alveolar septal cells (VC(L)→(L) air vs. VC(L)→(L) smoke vs. VC(L)→(S) smoke, 7.8 ± 1.1% vs. 4.9 ± 0.8% vs. 11.6 ± 3.3%) (Figure 6B ). We detected the same tendency for apoptosis and cell proliferation not only in alveolar septal cells but also in bronchial cells adjacent to alveolar ducts (data not shown). The representative results of immunohistochemistry for Ki-67 antibody in the lungs from each group at 8 months of age are shown in Figure 6C . A larger number of airway epithelial and alveolar septal cells were immunopositive for Ki-67 antibody (nuclei stained brown) in the VC(L)→(S) smoke group compared with the other three groups. Our results suggest that VC treatment not only lessened apoptosis but also improved cell proliferation in the lungs.

Discussion

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This is the first study using mice in which smoke-induced pulmonary emphysema is prevented and in which tissues damaged by previously established emphysema are repaired. Our results indicate that VC treatment after cessation of smoke exposure increased mRNA transcripts of collagen; ameliorated oxidative stress, inflammation, and alveolar septal cell apoptosis; and promoted cell proliferation and hence reconstituted the alveolar maintenance program in the lungs of SMP30-KO mice (Figure 7 ). SMP30-KO mice, like humans, lack the ability to synthesize VC (12), and these mice are a novel animal model of senile lungs because they develop an airspace enlargement prematurely without apparent parenchymal destruction (14). In this study, the emphysema in SMP30-KO mice was caused by prolonged exposure to cigarette smoke, and the destruction of alveolar tissue, oxidative stress, and inflammation in the lungs did not subside after the smoke exposure ceased. Furthermore, the emphysema in SMP30-KO mice caused by chronic cigarette smoke inhalation led to a mutual interaction among inflammation, oxidative stress, alveolar cell apoptosis, the decrease of ECM proteins, and the disruption of the alveolar maintenance program and was demonstrated to have mechanical properties similar to human COPD. These sequelae closely resembled the physiological properties of human COPD. Our results further illustrate that SMP30-KO mice would be a valuable experimental model of COPD.

Recent progress in exploring the pathogenic mechanisms of COPD has given rise to the novel concept that the lung structure maintenance program, in which the mutual interaction among numerous factors, including oxidative stress, inflammation, proteinase–antiproteinase imbalance, and aging, coalesce to cause this program's malfunction and the eventual emergence of emphysema involving enhanced senescence and alveolar apoptosis (1, 23). VEGF is a pluripotent growth factor that has a broad impact on endothelial cell survival and its function and plays a critical role in the maintenance of lung structure (1, 24–27). Experimental emphysema in animals has been produced by disruption of VEGF signaling or lung-targeted VEGF inactivation (27), and studies in human lungs have demonstrated decreased expression of VEGF and VEGF receptor-2 expression in association with emphysema (25). The disruption of VEGF signaling generates oxidative stress resulting in alveolar septal cell apoptosis, which in turn generates oxidative stress (28). In our experiments, VC treatment, after the cessation of smoke exposure, subsided oxidative stress and alveolar septal cell apoptosis and restored the concentration of VEGF in the BALF and in the lungs to the same level as that of the VC(L)→(L) air group. In contrast, oxidative stress and inflammation persisted and VEGF in the lungs remained diminished in the VC(L)→(L) smoke-exposed group (no VC treatment) even after cessation of cigarette smoke exposure. These observations support the speculation that VC treatment revitalized the lung structure maintenance program via amelioration of oxidative stress and alveolar septal cell apoptosis.

VC is not only a potent antioxidant but also plays an essential role in collagen synthesis by promoting the activity of the prolyl hydroxylase and by increasing the mRNA transcripts of collagen (29–33). In addition, VC is abundant in fluids of the lung epithelial lining (34). Recent human-based studies indicate that VC may be involved in the etiology of COPD (4–6). Smoking is also associated with unhealthy patterns of VC intake (35–37), and the metabolic turnover of VC in smokers is markedly higher than in nonsmokers (38, 39). In addition, a prospective study examining the relationship between dietary intake of antioxidant vitamins (vitamins A, C, and E) and decline of lung function performed in a general population consisting of 2,663 adults aged 18 to 70 years living in the United Kingdom identified a significant correlation between declining lung function and VC intake but not vitamins A or E (4). Siedlinski and colleagues recently reported that an interaction between functional polymorphisms of glutamate-cysteine ligase, an endogenously acting antioxidant enzyme, smoking, and low VC intake contributed to the oxidative burden and was associated with a loss of lung function (6).

In the present study, VC treatment increased collagen I and IV and promoted cell proliferation in the lungs of SMP30-KO mice. Collagen I is necessary for the maintenance of pulmonary structure, and collagen IV is a requirement of angiogenesis (22). Because the metabolism of pulmonary ECM is clearly associated with the development of emphysema, several studies of emphysema have focused on the breakdown of collagen (21, 40, 41). The breakdown of collagen by transgenic expression of collagenase in mice generated emphysema (21), and cigarette smoke–induced emphysema in guinea pigs involved a breakdown of collagen without significant changes in elastin (40). Furthermore, VC is a cofactor for enzymes required for ECM synthesis, including collagen prolyl hydroxylase and prolyl hydroxylase as well as proteins critical for tissue regeneration and the development of stem cells, such as hypoxia-inducible factor and histone demethylases (42). Histone demethylases regulate histone methylation associated with gene repression or activation and hence are essential for maintaining transcriptional programs and determining cell fate and identity. They modulate the expression of the embryonic stem cells master transcription factor Nanog (43). As also reported, VC enhanced the establishment (44) and differentiation of induced pluripotent stem cells through promoting the proliferation of progenitor cells (45), whereas alternative antioxidants failed to mimic the promoting role of VC in induced pluripotent stem cells (45) and in embryonic stem cells (46, 47). These findings may support the speculation that the inherent ability of synthesizing VC contributes to rapid alveolar repair mechanisms in wild-type mice that can synthesize VC (48). The broad spectrum of functions that VC exerts in the lungs may be superior for lung restoration in humans who, like SMP30-KO mice, cannot synthesize VC, compared with simple delivery of tissue stem cells and promotion of their proliferation and differentiation.

This study includes a limitation. We used genetically modified mice to demonstrate that VC has the capacity to repair lung tissue damaged by prolonged cigarette smoking. Genetically modified mice are often used for investigating the pathogenesis of emphysema. However, the possibility cannot be excluded that emphysema seen in genetically modified mice was caused by developmental abnormalities. We previously reported that VC plays an important role in lung development in SMP30-KO mice, and a complete lack of VC in the lungs generated emphysema (15). Thus, the possibility exists that the lack of SMP30 and the low intake of VC, which is sufficient to prevent mice from developing scurvy, affected lung development in this study. Therefore, the success of VC treatment for smoke-induced emphysema reported here should be confirmed by further studies using other animals (e.g., guinea pigs) that cannot synthesize VC inherently like humans.

In conclusion, SMP30-KO mice chronically exposed to cigarette smoke appear to show a pathobiology of emphysema very similar to that of human COPD. Because VC prevents cigarette smoke–induced emphysema and provides pulmonary restoration in SMP30-KO mice, which, like humans, lack the ability to synthesize VC, our results may provide a new therapeutic strategy for COPD.

The authors thank Ms. Phyllis Minick for excellent assistance in the review of English and Dr. Jun Furuhata, Ph.D., for technical assistance in preparing lung specimens.

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This work was supported by the High Technology Research Center Grant from the Ministry of Education, Culture, Sports, Science, and Technology; the Smoking Science Foundation (S.K. and I.A.); the Respiratory Failure Research Group from the Ministry of Health, Labor and Welfare, Japan (S.K.); and the Institute for Environmental and Gender-Specific Medicine, Juntendo University Graduate School of Medicine (S.K.).

Author Contributions: Conception and design: K.K., A.I., T.S., and K.S. Analysis and interpretation: K.K., Y.S., T.H., Y.Y., E.K., K.T., and M.S. Drafting the manuscript for important intellectual content: K.K., K.T., Y.F., N.M., and K.S.

This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org.

Originally Published in Press as DOI: 10.1165/rcmb.2013-0121OC on September 13, 2013

Author disclosures are available with the text of this article at www.atsjournals.org.

Is Vitamin C Good For Copd

Source: https://www.atsjournals.org/doi/full/10.1165/rcmb.2013-0121OC

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