Nitric oxide and regulators of its synthesis in chronic obstructive pulmonary disease

Abstract

ABSTRACT

The clinical picture and long-term prognosis of chronic obstructive pulmonary disease (COPD) largely depend on comorbid conditions, thereby prompting a relevant search for predictive and preventive methods in the pathogenesis of the disease. Cardiovascular diseases are highly prevalent among patients with COPD. Cardiovascular risks in patients with COPD are associated with changes in the activity of vasoactive mediators, with nitric oxide (NO) being the most important. The important role of nitric oxide in the body prompts it being studied as a biomarker of many diseases; however, its short half-life and rapid clearance prevent its direct assessment in the blood. In the body, nitric oxide is formed from L-arginine with the help of enzymes of NO-synthase group. NO oxide synthesis depends on the concentration of L-arginine, arginase and asymmetric dimethylarginine (inhibitory effect on NO-synthase). The presented literature review highlights modern views on the importance of nitric oxide and regulators of its synthesis in the pathogenesis of chronic obstructive pulmonary disease. It also indicates their role in the formation of comorbid conditions, and highlights processes of NO formation in the body.

CONCLUSION: The components of the nitric oxide system (nitric oxide metabolites, L-arginine, arginase, dimethylarginine dimethylaminohydrolase, asymmetric and symmetric dimethylarginine) can be considered as potential biomarkers of COPD, especially in conditions of cardiovascular comorbidity. Further studies on the nitric oxide system are recommended for assessing the prognosis of the course of diseases and the effectiveness of the current therapy.

Keywords

chronic obstructive pulmonary disease / nitric oxide / ADMA / arginase

References

[1] Singh D, Agusti A, Anzueto A, et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019. The European Respiratory Journal. 2019;53(5):1900164. doi: 10.1183/13993003.00164-2019

[2] Singh D., Agusti A., Anzueto A., et al. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Lung Disease: the GOLD science committee report 2019 // The European Respiratory Journal. 2019. Vol. 53, № 5. P. 1900164. doi: 10.1183/13993003.00164-2019

[3] Urban MH, Eickhoff P, Funk G-C, et al. Increased brachial intima-media thickness is associated with circulating levels of asymmetric dimethylarginine in patients with COPD. International Journal of Chronic Obstructive Pulmonary Disease. 2017;12:169–176. doi: 10.2147/COPD.S118596

[4] Urban M.H., Eickhoff P., Funk G.-C., et al. Increased brachial intima-media thickness is associated with circulating levels of asymmetric dimethylarginine in patients with COPD // International Journal of Chronic Obstructive Pulmonary Disease. 2017. Vol. 12. P. 169–176. doi: 10.2147/COPD.S118596

[5] Csoma B, Bikov A, Nagy L, et al. Dysregulation of the endothelial nitric oxide pathway is associated with airway inflammation in COPD. Respiratory Research. 2019;20(1):156. doi: 10.1186/s12931-019-1133-8

[6] Csoma B., Bikov A., Nagy L., et al. Dysregulation of the endothelial nitric oxide pathway is associated with airway inflammation in COPD // Respiratory Research. 2019. Vol. 20, № 1. P. 156. doi: 10.1186/s12931-019-1133-8

[7] Uryasyev OM, Nikitina IN, Shakhanov AV, et al. Comprehensive assessment of endothelial dysfunction using compression oscillometry and determination of the level of asymmetric dimethyl arginine in patients with bronchial asthma. Nauka Molodykh (Eruditio Juvenium). 2020;8(3):363–9. (In Russ). doi: 10.23888/HMJ202083363-369

[8] Урясьев О.М., Никитина И.Н., Шаханов А.В., и др. Комплексная оценка эндотелиальной дисфункции с использованием компрессионной осциллометрии и определением уровня асимметричного диметиларгинина у больных бронхиальной астмой // Наука молодых (Eruditio Juvenium). 2020. Т. 8, № 3. С. 363–369. doi: 10.23888/HMJ202083363-369

[9] Uryas’ev OM, Shakhanov AV. Role of nitric oxide synthases polymorphism in the development of comorbidity of bronchial asthma and hypertension. Kazan Medical Journal. 2017;98(2):226–32. (In Russ). doi: 10.17750/KMJ2017-226

[10] Урясьев О.М., Шаханов А.В. Роль полиморфизма синтаз оксида азота в формировании коморбидной патологии — бронхиальной астмы и гипертонической болезни // Казанский медицинский журнал. 2017. Т. 98, № 2. С. 226–232. doi: 10.17750/KMJ2017-226

[11] Ruzsics I, Nagy L, Keki S, et al. L-arginine Pathway in COPD Patients with Acute Exacerbation: A New Potential Biomarker. COPD. 2016;13(2):139–45. doi: 10.3109/15412555.2015.1045973

[12] Ruzsics I., Nagy L., Keki S., et al. L-arginine Pathway in COPD Patients with Acute Exacerbation: A New Potential Biomarker // COPD. 2016. Vol. 13, № 2. P. 139–145. doi: 10.3109/15412555.2015.1045973

[13] Shakhanov AV, Nikiforov AA, Uryasev OM. Polymorphism of nitric oxide synthase genes (NOS1 84G/A and NOS3 786C/T) in patients with bronchial asthma and essential hypertension. I.P. Pavlov Russian Medical Biological Herald. 2017;25(3):378–90. (In Russ). doi: 10.23888/PAVLOVJ20173378-390

[14] Шаханов А.В., Никифоров А.А., Урясьев О.М. Полиморфизм генов синтаз оксида азота (NOS1 84G/A и NOS3 786C/T) у больных бронхиальной астмой и гипертонической болезнью // Российский медико-биологический вестник имени академика И.П. Павлова. 2017. Vol. 25, № 3. С. 378–390. doi: 10.23888/PAVLOVJ20173378-390

[15] Fleming I Molecular mechanisms underlying the activation of eNOS. Pflügers Archiv - European Journal of Physiology. 2010;459(6):793–806. doi: 10.1007/s00424-009-0767-7

[16] Fleming I. Molecular mechanisms underlying the activation of eNOS // Pflügers Archiv — European Journal of Physiology. 2010. Vol. 459, № 6. P. 793–806. doi: 10.1007/s00424-009-0767-7

[17] Chen Y, Xu X, Sheng M, et al. PRMT-1 and DDAHs-induced ADMA upregulation is involved in ROS- and RAS-mediated diabetic retinopathy. Experimental Eye Research. 2009;89(6):1028–34. doi: 10.1016/j.exer.2009. 09.004

[18] Chen Y., Xu X., Sheng M., et al. PRMT-1 and DDAHs-induced ADMA upregulation is involved in ROS- and RAS-mediated diabetic retinopathy // Experimental Eye Research. 2009. Vol. 89, № 6. P. 1028–1034. doi: 10.1016/j.exer.2009.09.004

[19] Kharitonov SA, Lubec G, Lubec B, et al. L-arginine increases exhaled nitric oxide in normal human subjects. Clinical Science (London, England : 1979). 1995;88(2):135–9. doi: 10.1042/cs0880135

[20] Kharitonov S.A., Lubec G., Lubec B., et al. L-arginine increases exhaled nitric oxide in normal human subjects // Clinical Science (London, England : 1979). 1995. Vol. 88, № 2. P. 135–139. doi: 10.1042/cs0880135

[21] Morris CR, Poljakovic M, Lavrisha L, et al. Decreased arginine bioavailability and increased serum arginase activity in asthma. American Journal of Respiratory and Critical Care Medicine. 2004;170(2):148–53. doi: 10.1164/rccm.200309-1304OC

[22] Morris C.R., Poljakovic M., Lavrisha L., et al. Decreased arginine bioavailability and increased serum arginase activity in asthma // American Journal of Respiratory and Critical Care Medicine. 2004. Vol. 170, № 2. P. 148–153. doi: 10.1164/rccm.200309-1304OC

[23] Bratt JM, Zeki AA, Last JA, et al. Competitive metabolism of L-arginine: Arginase as a therapeutic target in asthma. Journal of Biomedical Research. 2011;25(5):299–308. doi: 10.1016/S1674-8301(11)60041-9

[24] Bratt J.M., Zeki A.A., Last J.A., et al. Competitive metabolism of L-arginine: Arginase as a therapeutic target in asthma // Journal of Biomedical Research. 2011. Vol. 25, № 5. P. 299–308. doi: 10.1016/S1674-8301(11)60041-9

[25] Mangoni AA, Rodionov RN, McEvoy M, et al. New horizons in arginine metabolism, ageing and chronic disease states. Age and Ageing. 2019;48(6):776–782. doi: 10.1093/ageing/afz083

[26] Mangoni A.A., Rodionov R.N., McEvoy M., et al. New horizons in arginine metabolism, ageing and chronic disease states // Age and Ageing. 2019. Vol. 48, № 6. P. 776–782. doi: 10.1093/ageing/afz083

[27] Bergeron C, Boulet LP, Page N, et al. Influence of cigarette smoke on the arginine pathway in asthmatic airways: increased expression of arginase I. The Journal of Allergy and Clinical Immunology. 2007;119(2):391–7. doi: 10.1016/j.jaci.2006.10.030

[28] Bergeron C., Boulet L.-P., Page N., et al. Influence of cigarette smoke on the arginine pathway in asthmatic airways: increased expression of arginase I // The Journal of Allergy and Clinical Immunology. 2007. Vol. 119, № 2. P. 391–397. doi: 10.1016/j.jaci.2006.10.030

[29] Xu W, Comhair SAA, Janocha AJ, et al. Arginine metabolic endotypes related to asthma severity. PloS One. 2017;12(8):e0183066. doi: 10.1371/journal.pone.0183066

[30] Xu W., Comhair S.A.A., Janocha A.J., et al. Arginine metabolic endotypes related to asthma severity // PloS One. 2017. Vol. 12, № 8. P. e0183066. doi: 10.1371/journal.pone.0183066

[31] Scrimini S, Pons J, Agustí A, et al. Differential effects of smoking and COPD upon circulating myeloid derived suppressor cells. Respiratory Medicine. 2013;107(12):1895–903. doi: 10.1016/j.rmed.2013.08.002

[32] Scrimini S., Pons J., Agustí A., et al. Differential effects of smoking and COPD upon circulating myeloid derived suppressor cells // Respiratory Medicine. 2013. Vol. 107, № 12. P. 1895–1903. doi: 10.1016/j.rmed.2013.08.002

[33] Guzmán-Grenfell A, Nieto-Velázquez N, Torres-Ramos Y et al. Increased platelet and erythrocyte arginase activity in chronic obstructive pulmonary disease associated with tobacco or wood smoke exposure. Journal of Investigative Medicine. 2011;59(3):587–92. doi: 10.2310/JIM.0b013e31820bf475

[34] Guzmán-Grenfell A., Nieto-Velázquez N., Torres-Ramos Y., et al. Increased platelet and erythrocyte arginase activity in chronic obstructive pulmonary disease associated with tobacco or wood smoke exposure // Journal of Investigative Medicine. 2011. Vol. 59, № 3. P. 587–592. doi: 10.2310/JIM.0b013e31820bf475

[35] Hodge S, Matthews G, Mukaro V, et al. Cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine. American Journal of Respiratory Cell and Molecular Biology. 2011;44(5):673–81. doi: 10.1165/rcmb.2009-0459OC

[36] Hodge S., Matthews G., Mukaro V., et al. Cigarette smoke-induced changes to alveolar macrophage phenotype and function are improved by treatment with procysteine // American Journal of Respiratory Cell and Molecular Biology. 2011. Vol. 44, № 5. P. 673–681. doi: 10.1165/rcmb.2009-0459OC

[37] Pera T, Zuidhof AB, Smit M, et al. Arginase inhibition prevents inflammation and remodeling in a guinea pig model of chronic obstructive pulmonary disease. The Journal of Pharmacology and Experimental Therapeutics. 2014;349(2):229–38. doi: 10.1124/jpet.113.210138

[38] Pera T., Zuidhof A.B., Smit M., et al. Arginase inhibition prevents inflammation and remodeling in a guinea pig model of chronic obstructive pulmonary disease // The Journal of Pharmacology and Experimental Therapeutics. 2014. Vol. 349, № 2. P. 229–238. doi: 10.1124/jpet.113.210138

[39] Scott JA, Gauvreau GM, Grasemann H. Asymmetric dimethylarginine and asthma. European Respiratory Journal. 2014;43(2):647–8. doi: 10.1183/09031936.00080313

[40] Scott J.A., Gauvreau G.M., Grasemann H. Asymmetric dimethylarginine and asthma // European Respiratory Journal. 2014. Vol. 43, № 2. P. 647–648. doi: 10.1183/09031936.00080313

[41] Maarsingh H, Zaagsma J, Meurs H. Arginase: A key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives. British Journal of Pharmacology. 2009;158(3):652–64. doi: 10.1111/j.1476-5381.2009.00374.x

[42] Maarsingh H., Zaagsma J., Meurs H. Arginase: A key enzyme in the pathophysiology of allergic asthma opening novel therapeutic perspectives // British Journal of Pharmacology. 2009. Vol. 158, № 3. P. 652–664. doi: 10.1111/j.1476-5381.2009.00374.x

[43] Maarsingh H, Bossenga BE, Bos IST, et al. L-arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction. European Respiratory Journal. 2009;34(1):191–9. doi: 10.1183/09031936.00105408

[44] Maarsingh H., Bossenga B.E., Bos I.S.T., et al. L-arginine deficiency causes airway hyperresponsiveness after the late asthmatic reaction // European Respiratory Journal. 2009. Vol. 34, № 1. P. 191–199. doi: 10.1183/09031936.00105408

[45] Jung C, Quitter F, Lichtenauer M, et al. Increased arginase levels contribute to impaired perfusion after cardiopulmonary resuscitation. European Journal of Clinical Investigation. 2014;44(10):965–71. doi: 10.1111/eci.12330

[46] Jung C., Quitter F., Lichtenauer M., et al. Increased arginase levels contribute to impaired perfusion after cardiopulmonary resuscitation // European Journal of Clinical Investigation. 2014. Vol. 44, № 10. P. 965–971. doi: 10.1111/eci.12330

[47] Nara A, Nagai H, Shintani–Ishida K, et al. Pulmonary arterial hypertension in rats due to age-related arginase activation in intermittent hypoxia. American Journal of Respiratory Cell and Molecular Biology. 2015;53(2):184–92. doi: 10.1165/rcmb.2014-0163OC

[48] Nara A., Nagai H., Shintani–Ishida K., et al. Pulmonary arterial hypertension in rats due to age-related arginase activation in intermittent hypoxia // American Journal of Respiratory Cell and Molecular Biology. 2015. Vol. 53, № 2. P. 184–192. doi: 10.1165/rcmb.2014-0163OC

[49] Rabe KF, Watz H Chronic obstructive pulmonary disease. The Lancet. 2017;389(10082):1931–40. doi: 10.1016/S0140-6736(17)31222-9

[50] Rabe K.F., Watz H. Chronic obstructive pulmonary disease // The Lancet. 2017. Vol. 389, № 10082. P. 1931–1940. doi: 10.1016/S0140-6736(17)31222-9

[51] Wang X-P, Zhang W, Liu X-Q, et al. Arginase I enhances atherosclerotic plaque stabilization by inhibiting inflammation and promoting smooth muscle cell proliferation. European Heart Journal. 2014;35(14):911–9. doi: 10.1093/eurheartj/eht329

[52] Wang X.-P., Zhang W., Liu X.-Q., et al. Arginase I enhances atherosclerotic plaque stabilization by inhibiting inflammation and promoting smooth muscle cell proliferation // European Heart Journal. 2014. Vol. 35, № 14. P. 911–919. doi: 10.1093/eurheartj/eht329

[53] Bitner BR, Brink DC, Mathew LC, et al. Impact of arginase II on CBF in experimental cortical impact injury in mice using MRI. Journal of Cerebral Blood Flow and Metabolism. 2010;30(6):1105–9. doi: 10.1038/jcbfm.2010.47

[54] Bitner B.R., Brink D.C., Mathew L.C., et al. Impact of arginase II on CBF in experimental cortical impact injury in mice using MRI // Journal of Cerebral Blood Flow and Metabolism. 2010. Vol. 30, № 6. P. 1105–1109. doi: 10.1038/jcbfm.2010.47

[55] Vallance P, Leiper J Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24(6):1023–30. doi: 10.1161/01.ATV.0000128897.54893.26

[56] Vallance P., Leiper J. Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway // Arteriosclerosis, Thrombosis, and Vascular Biology. 2004. Vol. 24, № 6. P. 1023–1030. doi: 10.1161/01.ATV.0000128897.54893.26

[57] 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(6):717–27. doi: 10.1007/s00408-017-0047-9

[58] Vögeli A., Ottiger M., Meier M.A., et al. Asymmetric Dimethylarginine Predicts Long-Term Outcome in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease // Lung. 2017. Vol. 195, № 6. P. 717–727. doi: 10.1007/s00408-017-0047-9

[59] Tajti G, Gesztelyi R, Pak K, et al. Positive correlation of airway resistance and serum asymmetric dimethylarginine level in copd patients with systemic markers of low-grade inflammation. International Journal of Chronic Obstructive Pulmonary Disease. 2017;12:873–84. doi: 10.2147/COPD.S127373

[60] Tajti G., Gesztelyi R., Pak K., et al. Positive correlation of airway resistance and serum asymmetric dimethylarginine level in copd patients with systemic markers of low-grade inflammation // International Journal of Chronic Obstructive Pulmonary Disease. 2017. Vol. 12. P. 873–884. doi: 10.2147/COPD.S127373

[61] Carraro S, Giordano G, Piacentini G, et al. Asymmetric dimethylarginine in exhaled breath condensate and serum of children with asthma. Chest. 2013;144(2):405–10. doi: 10.1378/chest.12-2379

[62] Carraro S., Giordano G., Piacentini G., et al. Asymmetric dimethylarginine in exhaled breath condensate and serum of children with asthma // Chest. 2013. Vol. 144, № 2. P. 405–410. doi: 10.1378/chest.12-2379

[63] Zinellu A, Fois AG, Mangoni AA, et al. Systemic concentrations of asymmetric dimethylarginine (ADMA) in chronic obstructive pulmonary disease (COPD): state of the art. Amino Acids. 2018;50(9):1169–76. doi: 10.1007/s00726-018-2606-7

[64] Zinellu A., Fois A.G., Mangoni A.A., et al. Systemic concentrations of asymmetric dimethylarginine (ADMA) in chronic obstructive pulmonary disease (COPD): state of the art // Amino Acids. 2018. Vol. 50, № 9. P. 1169–1176. doi: 10.1007/s00726-018-2606-7

[65] Hsu C-N, Lu P-C, Lo M-H, et al. The Association between Nitric Oxide Pathway, Blood Pressure Abnormalities, and Cardiovascular Risk Profile in Pediatric Chronic Kidney Disease. International Journal of Molecular Sciences. 2019;20(21):5301. doi: 10.3390/ijms20215301

[66] Hsu C.-N., Lu P.-C., Lo M.-H., et al. The Association between Nitric Oxide Pathway, Blood Pressure Abnormalities, and Cardiovascular Risk Profile in Pediatric Chronic Kidney Disease // International Journal of Molecular Sciences. 2019. Vol. 20, № 21. P. 5301. doi: 10.3390/ijms20215301

[67] Scott JA, North ML, Rafii M, et al. Asymmetric dimethylarginine is increased in asthma. American Journal of Respiratory and Critical Care Medicine. 2011;184(7):779–85. doi: 10.1164/rccm.201011-1810OC

[68] Scott J.A., North M.L., Rafii M., et al. Asymmetric dimethylarginine is increased in asthma // American Journal of Respiratory and Critical Care Medicine. 2011. Vol. 184, № 7. P. 779–785. doi: 10.1164/rccm.201011-1810OC

[69] Scott JA, Grasemann H. Asymmetric dimethylarginine: a disease marker for asthma? Chest. 2013;144(2):367–8. doi: 10.1378/chest.13-0480

[70] Scott J.A., Grasemann H. Asymmetric dimethylarginine: a disease marker for asthma? // Chest. 2013. Vol. 144, № 2. P. 367–368. doi: 10.1378/chest.13-0480

[71] Winnica DE, Scott JA, Grasemann H, et al. Chapter 19. Asymmetric-Dimethylarginine. In: Nitric Oxide. Biology and Pathobiology. 3rd ed. Elsiver; 2017. P. 247–54. doi: 10.1016/B978-0-12-804273-1.00019-3

[72] Winnica D.E., Scott J.A., Grasemann H., et al. Chapter 19. Asymmetric-Dimethylarginine. In: Nitric Oxide. Biology and Pathobiology. 3rd ed. Elsiver; 2017. P. 247–254. doi: 10.1016/B978-0-12-804273-1.00019-3

[73] Palm F, Onozato ML, Luo Z, et al. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems. American Journal of Physiology Heart and Circulatory Physiology. 2007;293(6):H3227–45. doi: 10.1152/ajpheart.00998.2007

[74] Palm F., Onozato M.L., Luo Z., et al. Dimethylarginine dimethylaminohydrolase (DDAH): expression, regulation, and function in the cardiovascular and renal systems // American Journal of Physiology. Heart and Circulatory Physiology. 2007. Vol. 293, № 6. P. H3227-Р3245. doi: 10.1152/ajpheart.00998.2007

[75] Antoniades C, Demosthenous M, Tousoulis D, et al. Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis. Hypertension. 2011;58(1):93–8. doi: 10.1161/HYPERTENSIONAHA.110.168245

[76] Antoniades C., Demosthenous M., Tousoulis D., et al. Role of asymmetrical dimethylarginine in inflammation-induced endothelial dysfunction in human atherosclerosis // Hypertension. 2011. Vol. 58, № 1. P. 93–98. doi: 10.1161/HYPERTENSIONAHA.110.168245

[77] Avci B, Alacam H, Dilek A, et al. Effects of asymmetric dimethylarginine on inflammatory cytokines (TNF-α, IL-6 and IL-10) in rats. Toxicology and Industrial Health. 2015;31(3):268–73. doi: 10.1177/0748233712472524

[78] Avci B., Alacam H., Dilek A., et al. Effects of asymmetric dimethylarginine on inflammatory cytokines (TNF-α, IL-6 and IL-10) in rats // Toxicology and Industrial Health. 2015. Vol. 31, № 3. P. 268–273. doi: 10.1177/0748233712472524

RIGHTS & PERMISSIONS

Uryasev O., Shakhanov A., Kanatbekova Z.