Silicosis and methylated arginines/L-arginines: case-control adapted a cross-sectional design

Abstract

Aim: Silicosis has long been recognized as an important occupational lung disease that is included in the group of pneumoconiosis. As already well-known silicosis is a progressive pneumoconiosis characterized by fibrosis in the lungs. Also, chronic exposure to silica may cause chronic obstructive pulmonary disease, emphysema, lung cancer, and pulmonary fibrosis. Asymmetric dimethyl arginine (ADMA), symmetric dimethyl arginine (SDMA), and L-NMMA (NG-mono-methylated-L-arginine) are the products of protein arginine methyltransferase (PRMT) enzymes. The aim of this study is to investigate the relationship between silicosis and arginine metabolites in silica exposed and non-exposed workers. Material and Method: 180 male subjects (90 non-exposed workers (age matched-control) and 90 workers diagnosed with silicosis occupational physician based on radiological and clinical findings and exposure history-(silica-exposed) were included in this study. The serum levels arginine, ADMA, SDMA, and L-NMMA were determined using enzyme-linked immunosorbent assay. Results: ADMA, SDMA, L-NMMA values were significantly higher in the silica-exposed group compared to the control group. The positive correlations were observed between methylated arginine parameters such as ADMA and SDMA, ADMA and L-NMMA levels (r=0.43, r=0.60; p<0.01). The negative correlations were found between SDMA and arginine/ADMA, L-NMMA, and arginine/ADMA, arginine and SDMA/ADMA, arginine/ADMA and SDMA/ADMA levels, respectively (r=-0.22; r=-0.22, r=-0.34, r=- 0.29; p<0.01). The strongest positive correlation was found between arginine and arginine/ADMA ratio, and the strongest negative relationship between ADMA and arginine/ADMA ratio, respectively (r=0.87; r= -0.48; p<0.01). Conclusion: The results could provide additional insight into understanding the disease and the potential for developing biomarkers.

Keywords

• Silicosis
• arginine
• ADMA
• SDMA
• L-NMMA

References

1. Chan JYW, Tsui JCC, Law PTW, et al. Regulation of TLR4 in silica-induced inflammation: An underlying mechanism of silicosis. Int J Med Sci 2018; 15: 986–91.
2. Dowsett L, Higgins E, Alanazi S, Alshuwayer NA, Leiper FC, Leiper J. ADMA: a key player in the relationship between vascular dysfunction and ınflammation in atherosclerosis. J Clin Med 2020; 9: 3026.
3. Patel RP, Levonen AL, Crawford JH, Darley-Usmar VM. Mechanisms of the pro- and anti-oxidant actions of nitric oxide in atherosclerosis. Vol. 47, Cardiovascular Research. Oxford Academic; 2000. p. 465–74.
4. Antoniades C, Shirodaria C, Leeson P, et al. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: Implications for endothelial function in human atherosclerosis. Eur Heart J 2009; 30: 1142–50.
5. Zhao Y, Hao C, Bao L, et al. Silica particles disorganize the polarization of pulmonary macrophages in mice. Ecotoxicol Environ Saf 2020; 193.
6. Oliva-Damaso E, Oliva-Damaso N, Rodriguez-Esparragon F, et al. Asymmetric (ADMA) and symmetric (SDMA) dimethylarginines in chronic kidney disease: A clinical approach. Int J Molecular Sci. MDPI AG 2019; 20: 3668.
7. Koudelka A, Ambrozova G, Klinke A, et al. Nitro-oleic acid prevents hypoxia- and asymmetric dimethylarginine-ınduced pulmonary endothelial dysfunction. Cardiovasc Drugs Ther 2016; 30: 579–86.
8. Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine: dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 2004; 24: 1023–30.

9. Zewinger S, Kleber ME, Rohrer L, et al. Symmetric dimethylarginine, high-density lipoproteins and cardiovascular disease. Eur Heart J 2017; 38: 1597–607.
10. Szabo Z, Bartha E, Nagy L, Molnar T. Increased symmetric dimethylarginine, but not asymmetric dimethylarginine, concentrations are associated with transient myocardial ischemia and predict outcome. J Int Med Res 2020; 48: 6.
11. Wells SM, Buford MC, Migliaccio CT, Holian A. Elevated asymmetric dimethylarginine alters lung function and induces collagen deposition in mice. Am J Respir Cell Mol Biol 2009; 40: 179–88.
12. Vögeli A, Ottiger M, Meier MA, et al. Asymmetric Dimethylarginine Predicts long-term outcome in patients with acute exacerbation of chronic obstructive pulmonary disease. Lung 2017; 195: 717–27.
13. Fernández Álvarez R, Martínez González C, Quero Martínez A, Blanco Pérez JJ, Carazo Fernández L, Prieto Fernández A. Guidelines for the Diagnosis and Monitoring of Silicosis. Arch Bronconeumol 2015; 51: 86–93.
14. Molnar T, Pusch G, Papp V, et al. The L-arginine pathway in acute ischemic stroke and severe carotid stenosis: Temporal profiles and association with biomarkers and outcome. J Stroke Cerebrovasc Dis 2014; 23: 2206–14.
15. Hosinian M, Qujeq D, Ahmadi Ahangar A. The relation between GABA and L-arginine levels with some stroke risk factors in acute ischemic stroke patients. Int J Mol Cell Med Spring 2016; 5: 100-5.
16. Maarsingh H, Pera T, Meurs H. Arginase and pulmonary diseases. Vol. 378, Naunyn-Schmiedeberg’s Archives of Pharmacology 2008. p. 171–84.
17. Parmaksiz E, Inal A, Salepci B, et al. Relationship of asymmetric dimethylarginine levels with disease severity and pulmonary hypertension in chronic obstructive pulmonary disease. Lung India 2018; 35: 199–203.
18. Tadié JM, Henno P, Leroy I, et al. Role of nitric oxide synthase/arginase balance in bronchial reactivity in patients with chronic obstructive pulmonary disease. Am J Physiol - Lung Cell Mol Physiol 2008; 294: 3.
19. Fajardo I, Svensson L, Bucht A, Pejler G. Increased levels of hypoxia-sensitive proteins in allergic airway inflammation. Am J Respir Crit Care Med 2004; 170: 477–84.
20. Böger R, Hannemann J. Dual role of the L-arginine–ADMA–NO pathway in systemic hypoxic vasodilation and pulmonary hypoxic vasoconstriction. Vol. 10, Pulmonary Circulation. SAGE Publications Ltd; 2020. Apr-Jun; 10: 2.
21. Kitowska K, Zakrzewicz D, Königshoff M, et al. Functional role and species-specific contribution of arginases in pulmonary fibrosis. Am J Physiol Cell Mol Physiol 2008; 294: L34–45.
22. Ding M, Chen F, Shi X, Yucesoy B, Mossman B, Vallyathan V. Diseases caused by silica: Mechanisms of injury and disease development. Vol. 2, International Immunopharmacology. Elsevier; 2002. p. 173–82.
23. Rimal B, Greenberg AK, Rom N. Basic pathogenetic mechanisms in silicosis: Current understanding. Vol. 11, Current Opinion in Pulmonary Medicine. Lippincott Williams and Wilkins; 2005. p. 169–73.
24. Anlar HG, Bacanli M, İritaş S, et al. Effects of Occupational Silica Exposure on OXIDATIVE Stress and Immune System Parameters in Ceramic Workers in TURKEY. J Toxicol Environ Heal - Part A Curr Issues 2017; 80: 688–96.
25. Pollard KM. Silica, silicosis, and autoimmunity. Front Immunol 2016; 7: 97.
26. Liu H, Cheng Y, Yang J, et al. BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis. Cell Death Dis 2017; 8: 3.
27. Xue C, Chao-Yang B, Alicated H, et al. Distinct metabolic features in the plasma of patients with silicosis and dust-exposed workers in Chinaa case-control study. BMC Pulmonary Medicine 2021; 21.
28. Misson P, van den Brûle S, Barbarin V, Lison D, Huaux F. Markers of macrophage differentiation in experimental silicosis. J Leukoc Biol 2004; 76: 926–32.
29. Miao R, Ding B, Zhang Y, Xia Q, Li Y, Zhu B. Proteomic profiling change during the early development of silicosis disease. J Thorac Dis 2016; 8: 329–41.
30. Brinkmann SJH, Wörner EA, Buijs N, et al. The arginine/ADMA ratio is related to the prevention of atherosclerotic plaques in hypercholesterolemic rabbits when giving a combined therapy with atorvastatine and arginine. Int J Mol Sci 2015; 16: 12230–42.
31. Notsu Y, Yano S, Shibata H, Nagai A, Nabika T. Plasma arginine/ADMA ratio as a sensitive risk marker for atherosclerosis: Shimane CoHRE study. Atherosclerosis 2015; 239: 61–6.
32. Clemente GS, van Waarde A, Antunes IF, Dömling A, Elsinga PH. Arginase as a potential biomarker of disease progression: A molecular imaging perspective. Vol. 21, International Journal of Molecular Sciences. MDPI AG; 2020. p. 1–36.
33. Mussai F, Wheat R, Sarrou E, et al. Targeting the arginine metabolic brake enhances immunotherapy for leukaemia. Int J Cancer 2019; 145: 2201–8.
34. Tain YL, Hsu CN. Toxic dimethylarginines: Asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). Toxins (Basel) 2017; 9: 92.
35. Trocha M, Szuba A, Merwid-Lad A, Sozánski T. Effect of selected drugs on plasma asymmetric dimethylarginine (ADMA) levels. Pharmazie 2010; 65: 562–71.
36. Gao L, Zhang JH, Chen XX, et al. Combination of L-Arginine and L-Norvaline protects against pulmonary fibrosis progression induced by bleomycin in mice. Biomed Pharmacother 2019; 113: 108768.
37. Böger RH, Maas R, Schulze F, Schwedhelm E. Elevated levels of asymmetric dimethylarginine (ADMA) as a marker for cardiovascular disease and mortality. Clin Chem Lab Med 2005; 43: 1124–9.
38. Thakkar V, Stevens WM, Prior D, et al. N-terminal pro-brain natriuretic peptide in a novel screening algorithm for pulmonary arterial hypertension in systemic sclerosis: A case-control study. Arthritis Res Ther 2012; 14: 3.
39. Nardi J, Nascimento S, Göethel G, et al. Inflammatory and oxidative stress parameters as potential early biomarkers for silicosis. Clinica Chimica Acta 2018; 484: 305–13.
40. Telo S, Kırkıl G, Kuluöztürk M, Balin M, Deveci F. Can ADMA play a role in determining pulmonary hypertension related to chronic obstructive pulmonary disease? Clin Respir J 2018; 12: 1433–8.
41. Lopes-Pacheco M, Bandeira E, Morales MM. Cell-based therapy for silicosis. Stem Cells International 2016; doi.org/10.1155/2016/5091838.