Investigation of heavy metal exposure and trace element levels in acute exacerbatıon of COPD

1 Introductıon

Due to its high prevalence, increasing incidence, and severe personal, social, and economic costs around the world, chronic obstructive pulmonary disease (COPD) is a serious public health concern (Vikjord et al., 2022; Halpin et al., 2019). When the disease burden and mortality due to COPD are examined, great differences are observed between countries and even between different social groups within the same country (Marmot et al., 2019). COPD has become a disease that can be seen in young people and women due to environmental exposures such as the health effects of air and environmental pollution (Agusti et al., 2020; Agustí et al., 2019). Despite the rapid advances in technology, our knowledge of the underlying pathobiological mechanisms of COPD is still limited (Dransfield et al., 2019). Biomarkers with potential benefits are needed in the prognosis of COPD exacerbation (Corradi et al., 2009). Prevıous works showed that heavy metals induce the pathogenesis of COPD through uncontrolled oxidative stress and chronic inflammation (Bertin et al., 2006; Cohen et al., 2002). It should also be noted that DNA repair and disruption of barrier mechanisms may also contribute to this process (Kirschvink et al., 2006). In one study in Korea, researchers found a notable link between obstructive lung disease and lead and cadmium concentrations in serum (Kim et al., 2015). In this work, we assessed the potential relationship between heavy metal levels (Al, Cd, Pb, Cr, Ca, Mn, Co, Ni, Cu, As, Hg, Zn) and the severity of attacks and lung function using the COPD GOLD classification. We also examined the relationship between mortality in COPD patients and heavy metal levels.

2 Materıal and method

3 Validation of methods

We repeated the standard and sample measurements five times to increase the accuracy of the results and lower the relative standard deviation (<5%). We used Whole Blood L-1 Standard Reference Material (Seronorm™ Trace Elements, Norway) for the validation method. The 100 µg/L of Hafnium was used for the internal standard. The intra and inter-day precision of Standard Reference Materials based on the standard deviation of replicates was utilized for the quality control method.

4 Results

The study consisted of 100 healthy volunteer controls and 114 patients with acute exacerbation of COPD. Table 1 shows the demographic information of the COPD cases. BMI in COPD patients was lower in comparison with control group (p < 0.05). The levels of As, Al, Cd, Co, Ca, Cr, Mn, Ni, Cu, Hg, and Pb were higher in COPD patients (p < 0.001) (Table 2). The level of Zn was same with control (p = 0.489). The distribution of age, BMI, FEV, and vital values ​​in COPD cases according to the GOLD classification is shown in Table 3. The distribution of heavy metal levels in COPD cases according to the GOLD classification is shown in Table 4. Especially, Al, Ca, Co, Ni, Cu, As, Cd and Hg levels of Group 4 were higher compared to Group 1 (p < 0.001). Likewise, the Mn level was found to be increased (p < 0.05). However, Zn levels in group 4 were lower than group 1 (p < 0.001). The predicting factors in the COPD patient group were determined using multivariate regression analysis. Al, Ca, Mn, Co, As, and Hg heavy metals were determined to be independent risk factors in predicting COPD exacerbations (p < 0.05) (Table 5, Fig. 1). The correlation analysis of heavy metals with mortality is shown in Table 6. Cd, Al, Co, Ni, Pb, and, Hg levels were increased in COPD exacerbations that resulted in mortality (p < 0.05). Co, Pb, Cd, and, Hg were determined to be independent risk factors for mortality in COPD cases (p < 0.05) (Table 7, Fig. 2).

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Fig. 1

Mutlivariate regression plots in terms of predicting disease in COPD exacerbation patients.

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Fig. 2

Mutlivariate regression analysis graph in terms of mortality.

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5 Dıscussıon

In this work, we found that the levels of heavy metals (Pb, Cr, Al, As, Ca, Ni, Hg, Mn, Co, Cu, and Cd) were higher in the serum of individuals with acute exacerbation of COPD in comparison to the control group. At the same time, we found that serum heavy metal (Al, Ca, Mn, Co, Ni, Cu, As, Cd, Hg) levels increased with the severity of the disease. With a reduction of Zn levels in serum, the severity of the disease shows an increased manner. Moreover, in COPD patients with acute exacerbation, higher levels of Co, Cd, Hg, and Pb in serum are independent risk factors for mortality.

Cellular toxicity due to cadmium has been investigated under different headings such as DNA and membrane-functional changes, metalloenzyme interference, thiol protein changes, energy metabolism inhibition, and increased oxidative damage (Chen et al., 2009; Kirmizi et al., 2020). It is also well known that cadmium, an environmentally toxic substance, causes many respiratory diseases in humans (Leem et al., 2015; Zeng et al., 2016). A previous study showed that high concentrations of serum cadmium were correlated with reduced pulmonary function (Oh et al., 2014). Different investigations on the possible connection between cadmium exposure and COPD have produced mixed findings. In another study based in China, no correlation was found between serum cadmium levels and lung function in healthy children without COPD (Pan et al., 2020). In comparison with the control group, we observed higher serum cadmium levels in COPD cases. Again, in our study group, the serum cadmium levels of the patients in the gold 3 and gold 4 groups were found to be significantly higher than those of gold 1 and 2. These results we obtained to support the inverse relationship between serum cadmium levels and lung functions. In addition, in the study of Ya-Lin Jiang et al., they argued that serum cadmium concentration in COPD patients showed a positive correlation with inflammation (Jiang et al., 2022). Considering that the severity of inflammation increases with the severity of the disease, the higher serum cadmium levels of the patients in the gold 3 and gold 4 groups in our study support this result.

Glutathione (GSH) depletion is one of the important determinant of organ toxicities (Ahmadian et al., 2017; Eftekhari et al., 2016) and previous studies showed that mercury depletes GSH and causes oxidative stress and severe endothelial cell dysfunction, and leads to different lung diseases, such as bronchitis and pulmonary fibrosis (Tchounwou et al., 2003). In a study, it was observed that FEV 1 after bronchodilator decreased with increasing mercury concentrations (Heo et al., 2017). In our study, higher serum mercury levels were detected in the patient population in the acute COPD exacerbation gold 4 group. At the same time, one of the independent mortality risk factors was mercury levels. These results may indicate that mercury exposure may have severe clinical consequences. Arsenic (As) is a metalloid commonly found in soil and groundwater (Fatoki et al., 2022; Roy et al., 2020). Arsenic exposure, though not directly with COPD, has been strongly associated with decreased lung function and respiratory disease mortality in adults (Parvez et al., 2013; Sanchez, et al., 2018). Exposure to lead is linked to reduced lung function and a high risk of COPD (Leem et al., 2015, Gogoi et al., 2019). Chromium is also a metal associated with adverse effects on respiration, which is known to cause lung damage and cancer (Novey et al., 1983). The data obtained from your study show that high serum As levels increase with the severity of the disease, but Pb and Cr levels are not associated with the severity of the disease.

Cu is an important metal for many cellular functions such as antioxidant activity, iron transport, and collagen synthesis (Robinson et al., 2013). Higher levels of Cu increase inflammation and oxidative stress (Guo et al., 2013). Conversely, it is documented that in inflammation-related Peyronie's disease the level of serum Cu is low (Gunes et al., 2013). In another study conducted on patients with COPD, high serum Cu levels were found in the patient group with acute COPD attacks (Tanrikulu et al., 2011). Similarly, in cases with acute exacerbation, the levels of Cu in serum are high in our work. In addition, according to the gold classification, we found an increase in the serum Cu levels of the patients as the clinical severity of COPD exacerbation increased. In light of our findings, elevated serum copper levels may be an indicator of inflammation resulting from clinical aggravation of the disease. Again, in a study conducted on rheumatoid arthritis (inflammatory disease) patients, it was observed that copper levels were higher in serum (Önal et al., 2011).

It was reported that in patients with a critical situation the level of Zn decreased, especially in patients with sepsis (Mertens et al., 2015). In another work, Zn levels were low in critically ill patients with COPD (Karadag et al., 2004). In our investigation, the levels of Zn in serum are the same in both groups. However, in our patient group, levels of serum Zn were lower in patients with a more severe clinical picture (grade 2–3-4) according to the gold classification compared to milder patients (grade 1). This may indicate that zinc deficiency may cause more severe COPD exacerbations. In previous studies, it is known that the antioxidant enzyme superoxide dismutase contains Zn in its structurally active part (Chuapil et al., 1976, Huang et al., 1977). In line with the findings of our study, the possible excessive use of oxidant-antioxidant systems in patients with clinically severe acute COPD may have been effective in the reduction of zinc due to the use of zinc by those systems.

6 Limitations

This study has some limitations. First of all, the clarification of the cause-effect relationship between lung function and serum heavy metal levels is hard, since it is a case-control study. Secondly, no information about exposure (high dietary intake, smoking history, occupation, etc.) was obtained from the patients. We tried to examine the association between serum levels of heavy metal and pulmonary functions, regardless of any exposure. The relatively low number of patients can be counted as one of the limitations of this study.

7 Conclusion and future perspectives

Our study showed that serum heavy metal levels are linked with the harshness and mortality of acute COPD attacks. These findings may indicate that changes in serum heavy metal levels can be used to determine the severity of a COPD exacerbation. However, future studies with larger patient groups will be useful in clarifying the predictive role of heavy metals levels in serum as markers of disease status.