Oxidative Biomarkers Associated with the Pulmonary Manifestation of Post-COVID-19 Complications

Abstract

Introduction: The role of mitochondria in post coronavirus disease 2019 (post-COVID-19) complications is unclear, especially in the long-term pulmonary complications. This study aims to investigate the association between post-COVID-19 pulmonary complications and mitochondrial regulatory proteins in the context of oxidative stress.

Methodology: Patients who had recovered from COVID-19 were enrolled. According to the evidence of persistent interstitial lung lesions on computed tomography (CT), patients were divided into a long-term pulmonary complications group (P(+)) and a control group without long-term pulmonary complications (P(-)). We randomly selected 80 patients for investigation (40 subjects for each group). Biomarkers levels were determined by enzyme-linked immunosorbent assay (ELISA).

Results: The serum concentrations of mitochondrial regulatory proteins were significantly higher in the P(+) group, including PTEN-induced kinase 1 (PINK1): 1.62 [1.02-2.29] ng/mL vs. 1.34 [0.94-1.74] ng/mL (p = 0.046); Dynamin-1-like protein (DNM1L): 1.6 [0.9-2.4] ng/mL IQR vs. 0.9 [0.5-1.6] ng/mL (p = 0.004); and Mitofusin-2 (MFN2): 0.3 [0.2-0.5] ng/mL vs. 0.2 [0.1-0.3] ng/mL IQR (p = 0.001). Patients from the P(+) group also had higher serum levels of chemokine ligand 18 (PARC, CCL18), IL-6, and tumour necrosis factor-alpha (TNF-α) cytokines than the P(-) group. The concentration of interferon alpha (IFN-α) was decreased in the P(+) group. Furthermore, we observed statistically significant correlations between the advanced glycation end product (sRAGE) and TNF-α (Pearson's factor R = 0.637; p < 0.001) and between serum levels of DNM1L and IFN-α (Pearson's factor R = 0.501; p = 0.002) in P(+) patients.

Conclusions: Elevated concentrations of mitochondrial biomarkers in post-COVID-19 patients with long-term pulmonary complications indicate their possible role in the pathobiology of COVID-19 pulmonary sequelae. Oxidative stress is associated with the immune response and inflammation after COVID-19. TNF-α could be a promising biomarker for predicting pulmonary complications and may be a potential target for therapeutic intervention in patients with post-COVID-19 complications.

Keywords: CCL18; DNM1L; IFN-α; PINK1; SARS-CoV-2; TNF-α; mitophagy; oxidative stress; post-COVID-19; pulmonary fibrosis; sRAGE.

Scheme 1

Experiment design and patient selection for the ELISA tests.

Figure 1

The difference in pulmonary and activation-regulated chemokine (PARC, CCL18) cytokine levels between the investigated groups. P(+)—long-term pulmonary complications group; P(−)—no long-term pulmonary complications group; p = 0.036.

Figure 2

(A) Correlation between serum levels of soluble receptor for the advanced glycation end product (sRAGE) and tumor necrosis factor-alpha (TNF-α) in patients with long-term pulmonary complications (P(+)). Pearson’s factor R = 0.637; p < 0.001. (B) Correlation between serum levels of dynamin-1-like protein (DNM1L) and interferon-alpha (IFN-α) in patients with long-term pulmonary complications (P(+)). Pearson’s factor R = 0.501; p = 0.002; red solid line—regression line; red dashed lines—0.95 confidence interval.

Figure 2

(A) Correlation between serum levels of soluble receptor for the advanced glycation end product (sRAGE) and tumor necrosis factor-alpha (TNF-α) in patients with long-term pulmonary complications (P(+)). Pearson’s factor R = 0.637; p < 0.001. (B) Correlation between serum levels of dynamin-1-like protein (DNM1L) and interferon-alpha (IFN-α) in patients with long-term pulmonary complications (P(+)). Pearson’s factor R = 0.501; p = 0.002; red solid line—regression line; red dashed lines—0.95 confidence interval.

Figure 3

Correlation between serum levels of dynamin-1-like protein (DNM1L) and pulmonary and activation-regulated chemokine (PARC, CCL18) in patients with no long-term pulmonary complications (P(−)). Pearson’s factor R = 0.494; p = 0.003; red solid line—regression line; red dashed lines—0.95 confidence interval.

Figure 4

Comparison of the diagnostic value of biomarkers in prediction of the development of long-term pulmonary complications in patients who had recovered from COVID-19.