Biologically active molecules cytokines and growth factors (GFs) are critical regulators of tissue injury/repair and emerge as key players in COVID-19 pathophysiology. However, specific disease stage of GFs dysregulation and, whether these GFs have associations with thromboembolism and tissue injury/repair in COVID-19 remain vague. GF profiling in hospitalized moderate (non-ICU) and critically ill (ICU) COVID-19 patients was performed through legendPlex assay. Investigation revealed profound elevation of VEGF, PDGFs, EGF, TGF-α, FGF-basic, and erythropoietin (EPO) in moderate cases and decline or trend of decline with disease advancement. We found strong positive correlations of plasma VEGF, PDGFs, and EPO with endothelial dysfunction markers P-selectin and sCD40L. Interestingly, the HGF and G-CSF were upregulated at the moderate stage and remained elevated at the severe stage of COVID-19. Moreover, strong negative correlations of PDGFs (r2 = 0.238, P = 0.006), EPO (r2 = 0.18, P = 0.01) and EGF (r2 = 0.172, P = 0.02) and positive correlation of angiopoietin-2 (r2 = 0.267, P = 0.003) with D-dimer, a marker of thromboembolism, was observed. Further, plasma PDGFs (r2 = 0.199, P = 0.01), EPO (r2 = 0.115, P = 0.02), and EGF (r2 = 0.108, P = 0.07) exhibited negative correlations with tissue injury marker, myoglobin. Taken together, unlike cytokines, most of the assessed GFs were upregulated at the moderate stage of COVID-19. The induction of GFs likely occurs due to endothelial dysfunction and may counter the adverse effects of cytokine storms which is reflected by inverse correlations of PDGFs, EPO, and EGF with thromboembolism and tissue injury markers. The findings suggest that the assessed GFs play differential roles in the pathogenesis of COVID-19. 

https://doi.org/10.1016/j.lfs.2022.120703

SARS-CoV-2 infection- induced growth factors play differential roles in COVID-19 pathogenesis

D-dimer is an established biomarker of thromboembolism and severity in COVID-19. We and others have recently reported the dysregulation of tissue factor pathway inhibitor (TFPI), FXIII, fibrinolytic pathway, inflammatory markers, and tissue injury markers, particularly in severe COVID-19. However, association of these markers with thromboembolism in COVID-19 remains elusive. The correlation analyses between these markers in patients with moderate (non-ICU) and severe COVID-19 (ICU) were performed to delineate the potential pathomechanisms and impact of thromboembolism. We observe a negative correlation of plasma TFPI (r2 = 0.148, P = 0.035), FXIII (r2 = 0.242, P = 0.006), and plasminogen (r2 = 0.27, P = 0.003) with D-dimer, a biomarker of thromboembolism, levels in these patients. Further analysis revealed a strong positive correlation between fibrinolytic markers tissue plasminogen activator (tPA) and plasminogen activator inhibitor-1 (PAI-1) (r2 = 0.584, P < 0.0001). Interestingly, a significant positive correlation of PAI-1, but not tPA, was observed with platelets and endothelial cells dysfunction markers P-selectin (r2 = 0.184, P = 0.01) and soluble CD40 ligand (sCD40 L) (r2 = 0.163, P = 0.02). Moreover, calprotectin (S100A8/A9) and cystatin C (CST3), previously linked with thromboembolism, exhibited positive correlations with each other (r2 = 0.339, P = 0.0007) and with the level of D-dimer independently in COVID-19. Finally, the tissue injury marker myoglobin demonstrated a strong positive correlation with D-dimer (r2 = 0.408, P = 0.0001). Taken together, inverse correlations of TFPI and FXIII with D-dimer suggest the TF pathway activation and aberrant fibrin polymerization in COVID-19 patients. The elevated level of PAI-1 is potentially contributed by activated platelets and endothelial cells. S100A8/A9 may also play roles in impaired fibrinolysis and thromboembolism, in part, through regulating the CST3. These findings strengthen the understanding of thromboembolism and tissue injury and may help in better management of thromboembolic complications in COVID-19 patients.

TFPI and FXIII negatively and S100A8/A9 and Cystatin C positively correlate with D-dimer in COVID-19

Heart failure (HF) is often associated with compromised physical capacity in patients. However, it is unclear if established HF markers correlate with the physical performance of patients with congestive HF (CHF). We assessed the left ventricular end-systolic dimension (LVESD) and ejection fraction (LVEF) and, physical performance parameters, including short physical performance battery (SPPB), gait speed (GS), and handgrip strength (HGS) in 80 patients with CHF along with 59 healthy controls. Furthermore, levels of plasma HF markers galectin-3 and heart-specific fatty acid binding protein (H-FABP) were measured in relation to the severity of HF and physical performance. Irrespective of etiology, significantly greater LVESD and lower LVEF were observed in HF patients versus controls. As expected, the levels of HF markers galectin-3 and H-FABP were upregulated in the CHF patients which were accompanied by significantly elevated levels of plasma zonulin and inflammatory marker C-reactive protein (CRP). The SPPB scores, GS, and HGS were significantly lower in the ischemic and non-ischemic HF patients than controls. The level of galectin-3 was inversely correlated with SPPB scores (r2 = 0.089, P = 0.01) and HGS (r2 = 0.078, P = 0.01). Similarly, H-FABP levels were also inversely correlated with SPPB scores (r2 = 0.06, P = 0.03) and HGS (r2 = 0.109, P = 0.004) in the patients with CHF. Taken together, CHF adversely affects physical performance, and galectin-3 and H-FABP may serve as biomarkers of physical disability in patients with CHF. The robust correlations of galectin-3 and H-FABP with the physical performance parameters and CRP in CHF patients suggest that the poor physical performance may partly be caused due to systemic inflammation.

Plasma Galectin-3 and H-FABP correlate with poor physical performance in patients with congestive heart failure

Abstract Background Thromboembolism was a chief cause of mortality in 70% of patients with COVID-19. Our objective was to see if serum interleukins 1 beta (IL-1β) and soluble platelets selectin (sP-selectin) could serve as novel markers of thromboembolism in COVID-19 patients. Methods This cross sectional study involved 89 COVID-19 patients who were recruited from 1st of February to 1st of May 2021. Clinical and laboratory data were collected, and chest imaging was performed. The levels of IL-1β and sP-selectin were assessed in all cases through ELISA kits. Comparisons between groups were done using an unpaired t-test in normally distributed quantitative variables. In contrast, a non-parametric Mann-Whitney test was used for non-normally distributed quantitative variables. Results Severe COVID-19 infection was associated with higher serum levels of CRP, Ferritin, LDH, D dimer, IL-1β and sP-selectin ( P &lt; 0.001) with significant correlation between levels of IL-1β and sP-selectin (r 0.37, P &lt; 0.001), D-dimer (r 0.29, P 0.006) and Ferritin (r 0.5, p &lt; 0.001). Likewise, a positive correlation was also found between levels of sP-selectin, D-dimer and Ferritin (r 0.52, P &lt; 0.001) ( r 0.59, P &lt; 0.001 ) . Imaging studies revealed that 9 (10.1%) patients developed venous and 14 (15.7%) developed arterial thrombosis despite receiving anticoagulant therapy. Patients with thrombotic events had significantly higher levels of IL-1β, sP-selectin and LDH serum levels. Meanwhile, there was no statistical significance between CRP, D-dimer or Ferritin levels and the development of thrombotic events. Conclusion IL-1β and sP-selectin levels can be promising predictors for severe COVID-19 infection and predictable thrombosis. 

/pdf/serum-interleukin-1b-and-sp-selectin-as-biomarkers-of-3g0nxuab.pdf

Serum interleukin 1β and sP-selectin as biomarkers of inflammation and thrombosis, could they be predictors of disease severity in COVID 19 Egyptian patients? (a cross-sectional study)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection leads to various clinical symptoms including anemia. Lipocalin-2 has various biological functions, including defense against bacterial infections through iron sequestration, and it serves as a biomarker for kidney injury. In a human protein array, we observed increased lipocalin-2 expression due to parental SARS-CoV-2 infection in the Calu-3 human lung cancer cell line. The secretion of lipocalin-2 was also elevated in response to parental SARS-CoV-2 infection, and the SARS-CoV-2 Alpha, Beta, and Delta variants similarly induced this phenomenon. In a Calu-3 implanted mouse xenograft model, parental SARS-CoV-2 and Delta variant induced lipocalin-2 expression and secretion. Additionally, the iron concentration increased in the Calu-3 tumor tissues and decreased in the serum due to infection. In conclusion, SARS-CoV-2 infection induces the production and secretion of lipocalin-2, potentially resulting in a decrease in iron concentration in serum. Because the concentration of iron ions in the blood is associated with anemia, this phenomenon could contribute to developing anemia in COVID-19 patients.

SARS-CoV-2 infection induces expression and secretion of lipocalin-2 and regulates iron in a human lung cancer xenograft model.

Severe coronavirus (SARS-COV-2) infection often leads to systemic inflammation accompanied by cardiovascular complications including venous thromboembolism (VTE). However, it is largely undefined if inflammatory markers such as lipocalin-2 (LNC2), calprotectin (S100A8/A9), and cystatin C (CST3), previously linked with VTE, play roles in cardiovascular complications and advancement of COVID-19 severity. To investigate the same, hospitalized moderate and severe (presented pneumonia and required intensive care) COVID-19 patients were recruited. The levels of plasma LNC2, S100A8/A9, CST3, myoglobin, and cardiac Troponin I (cTnI) were assessed through enzyme-linked immunosorbent assay (ELISA). The investigation revealed a significantly upregulated level of plasma LNC2 at the moderate stage of SARS-CoV-2 infection. In contrast, the levels of S100A8/A9 and CST3 in moderate patients were comparable to healthy controls; however, a profound induction was observed only in severe COVID-19 patients. The tissue injury marker myoglobin was unchanged in moderate patients; however, a significantly elevated level was observed in the critically ill COVID-19 patients. In contrast, cTnI level was unchanged both in moderate and severe patients. Analysis revealed a positive correlation between the levels of S100A8/A9 and CST3 with myoglobin in COVID-19. In silico analysis predicted interactions of S100A8/A9 with toll-like receptor 4 (TLR-4), MyD88 LY96, and LCN2 with several other inflammatory mediators including MMP2, MMP9, TIMP1, and interleukins (IL-6, IL-17A, and IL-10). In summary, early induction of LCN2 likely plays a role in advancing the COVID-19 severity. A positive correlation of S100A8/A9 and CST3 with myoglobin suggests that these proteins may serve as predictive biomarkers for thromboembolism and tissue injury in COVID-19.

Lipocalin-2, S100A8/A9, and cystatin C: Potential predictive biomarkers of cardiovascular complications in COVID-19

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Lipocalin-2, S100A8/A9, and cystatin C: Potential predictive biomarkers of cardiovascular complications in COVID-19