Oxidative stress is known to contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD). Cigarette smoke contains high levels of oxidants, which also adds to the oxidative stress in COPD. Endogenous antioxidants are present to scavenge these harmful oxidants and help maintain lung homeostasis. An imbalance in oxidant-antioxidant levels in the lung is detrimental. Indeed, healthy smokers and COPD patients were found to have an impaired oxidant-antioxidant balance as determined by increased plasma levels of malonyldoaldehyde and decreased levels erythrocyte superoxide dismutase enzyme activity (Citation1).
Extracellular superoxide dismutase (EC-SOD or SOD 3) is one member of the superoxide dismutase family of antioxidant enzymes. EC-SOD is mainly located in the extracellular matrix and is highly expressed in arteries and the lung (Citation2). Numerous studies have shown that pulmonary EC-SOD inhibits lung injury in response to variety of pulmonary insults (Citation3–9). EC-SOD is known to limit inflammation and prevent oxidative damage by directly binding to and preventing the oxidative fragmentation of numerous extracellular matrix components, such as type I collagen (Citation10), heparan sulfate (Citation11, 12), and hyaluronan (Citation13). Therefore, inherited changes in EC-SOD expression and function could greatly influence lung homeostasis and proper pulmonary function.
There are 3 known single nucleotide polymorphisms (SNPs) in the SOD3 gene: E1 (rs8192287) in the noncoding 5’ untranslated region (Citation14); I1 (rs8192288) in the first intron (Citation14), and R213G (rs1799895) in the coding region for the carboxyl-terminal domain (Citation15). The R213G SNP is the most commonly studied polymorphism as the carboxyl-terminal domain is essential for its affinity to the extracellular matrix. Indeed, heterozygote carriers of this polymorphism have approximately 10-fold higher plasma concentrations of EC-SOD than non-carriers (Citation16), which is not observed with the other polymorphisms (Citation14).
Increased concentrations of EC-SOD in the plasma of R213G carriers is thought to be secondary to diffusion of EC-SOD from the matrices of tissues as a results of reduced affinity to heparin and collagen. Indeed, this mutation has been shown to markedly decrease EC-SOD's binding affinity to both heparin and collagen (Citation17). Importantly, the R213G SNP is known to increase the risk of ischemic heart disease in patients that have this polymorphism/mutation (Citation18). As EC-SOD is highly expressed in the matrix of arteries including coronary arteries (Citation19), it is thought that the R213G SNP leads to a loss of EC-SOD from the arterial walls due to decreased affinity to heparin and other matrix components. However, vascular levels of EC-SOD in patients with this sequence alteration have still not been examined.
The article by Sorheim et al. in this issue of the Journal of Chronic Obstructive Pulmonary Disease highlights the potential importance of EC-SOD polymorphisms in the lung, which like arteries also contains high levels of this antioxidant enzyme compared to most other tissues (Citation2, Citation20, Citation21). Previous studies have shown that polymorphisms in the SOD3 gene are associated with altered lung function and COPD. Dahl et al. were the first to identify E1 and I1 SNPs in the SOD3 gene and showed that individuals homozygous for these polymorphisms had greater risk of lower forced vital capacity and more frequent COPD hospitalizations than non-carriers (Citation14).
In contrast, 3 studies have found that the SOD3 R213G SNP has a protective effect in COPD. The study by Juul et al. found that smokers with the R213G SNP had a reduced risk of COPD (Citation22). In addition, Young et al. determined that smokers with this SNP were less likely to develop COPD suggesting this SNP promotes a COPD resistant phenotype in smokers (Citation23). Finally, a study by Siedlinski et al. has recently found this polymorphism is associated with a slower decline in FEV1, but only in never-smokers (Citation24).
In this issue, Sorheim et al. expand the present knowledge on SOD3 polymorphisms in COPD susceptibility. The authors genotyped three SNPs E1, I1, and R213G in a well-characterized case-cohort of ex- and current smokers and examined whether these SOD3 polymorphisms were associated with COPD status, lung function variables, and quantitative CT measurements of emphysema and airway wall thickness. Overall, they show a role for EC-SOD in the emphysema subtype of COPD by demonstrating an association between polymorphisms in the SOD3 gene and emphysema severity on chest CT scans.
This study is unique and interesting in the fact that it disagrees with prior studies showing a link between other COPD-related functional capacity measurements, like FEV1 and FVC%, and these polymorphisms and COPD susceptibility, but as the authors acknowledge, frequencies resulted in limited power to detect associations that may have contributed to this discrepancy. Regardless, this study further contributes valuable data as it suggests that EC-SOD may play an important role in the pathogenesis of COPD and highlights the need for further studies to determine how EC-SOD contributes to COPD pathogenesis and why different polymorphisms appear to have disparate effects on COPD susceptibility.
An important step in determining how these polymorphisms contribute to COPD pathogenesis will be to investigate their effects on EC-SOD expression and localization in the lung. Notably, both the E1 and I1 SNPs have been suggested to lead to decreased expression of EC-SOD in the lungs, although these changes were not statistically significant (Citation14). As pulmonary EC-SOD is known to inhibit degradation of several matrix components and inhibit inflammation, it may be that these polymorphisms promote COPD by decreasing tissue levels of EC-SOD, which then leads to enhanced inflammation and loss of alveolar parenchyma.
Although the link between EC-SOD levels in the lungs of humans with SOD3 polymorphisms and COPD-related phenotypes has not been fully investigated, a study by Ganguly et al. shows the correlation between SOD3 polymorphisms, lung EC-SOD expression, and pulmonary function in mice. In this study, JF1/Msf mice, with known decreased ventilation efficiency when compared to C3H/HeJ mice, were found to have 3 SOD3 promoter single nucleotide polymorphisms and decreased SOD3 transcript, protein expression, and activity in the lungs compared to C3H/HeJ mice (Citation25). This study illustrates that the genetic variants of SOD3 result in diminished pulmonary expression of EC-SOD, which correlates with decreased lung function and ultimately increased susceptibility to lung diseases.
Although there is a suggestion that the E1 and I1 SNPs lead to decreased pulmonary expression of EC-SOD, it is important to note that the R213G SNP is also predicted to lead to a loss of EC-SOD from the pulmonary interstitium due to a loss of EC-SOD affinity to components in the extracellular matrix. Indeed, this loss of matrix affinity is thought to explain why individuals with this SNP have a higher risk of ischemic heart disease. However, in contrast to the E1 and I1 SNPs, the R213G SNP has been suggested to perhaps offer a protective effect against COPD in 3 separate studies, although no effect was replicated in the current study by Sorheim et al.
The differences in effects of the E1 and I1 SNPs compared to the R213G SNP may be due to increase diffusion of EC-SOD into the alveolar lining fluid of the lung in a manner similar to the increases in plasma EC-SOD seen in patients with the R213G SNP, which would not occur with the E1 and I1 SNPs. This potential increase of EC-SOD in the alveolar lining fluid of patients with the R213G SNP may serve to act as an antioxidant shield that protects the lungs against oxidants present in cigarette smoke. This scenario is supported by the findings that the SOD3 R213G polymorphism correlates with decreased risk of COPD for smokers, but not non-smokers (Citation22, 23). Unfortunately, no studies to our knowledge have investigated the levels of EC-SOD in lung tissue and alveolar lining fluid of patients with the SOD3 R213G SNP. Thus, direct measurements of EC-SOD in the alveolar lining fluid will need to be done to determine if this hypothesis could explain how the R213G SNP offers protection against COPD.
As studies like Sorheim et al. in this issue of the Journal of Chronic Obstructive Pulmonary Disease continue to expand our knowledge of the correlation between SOD3 gene polymorphisms and lung function phenotypes, it is increasingly important that we determine how these polymorphisms affect the localization and expression of EC-SOD in these patients. Understanding the mechanism by which these SNPs contribute to disease pathogenesis may allow for the development of preventive interventions for patients with disease-associated polymorphisms.
Declaration of interest
The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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