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Open Access 01-12-2023 | Stroke | Research

Inhaled nitric oxide suppresses neuroinflammation in experimental ischemic stroke

Authors: Rebecca I. Sienel, Uta Mamrak, Janina Biller, Stefan Roth, Andreas Zellner, Tipparat Parakaw, Rayomand S. Khambata, Arthur Liesz, Christof Haffner, Amrita Ahluwalia, Burcu F. Seker, Nikolaus Plesnila

Published in: Journal of Neuroinflammation | Issue 1/2023

Abstract

Ischemic stroke is a major global health issue and characterized by acute vascular dysfunction and subsequent neuroinflammation. However, the relationship between these processes remains elusive. In the current study, we investigated whether alleviating vascular dysfunction by restoring vascular nitric oxide (NO) reduces post-stroke inflammation. Mice were subjected to experimental stroke and received inhaled NO (iNO; 50 ppm) after reperfusion. iNO normalized vascular cyclic guanosine monophosphate (cGMP) levels, reduced the elevated expression of intercellular adhesion molecule-1 (ICAM-1), and returned leukocyte adhesion to baseline levels. Reduction of vascular pathology significantly reduced the inflammatory cytokines interleukin-1β (Il-1β), interleukin-6 (Il-6), and tumor necrosis factor-α (TNF-α), within the brain parenchyma. These findings suggest that vascular dysfunction is responsible for leukocyte adhesion and that these processes drive parenchymal inflammation. Reversing vascular dysfunction may therefore emerge as a novel approach to diminish neuroinflammation after ischemic stroke and possibly other ischemic disorders.

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Feigin VL, et al. World Stroke Organization (WSO): global stroke fact sheet 2022. Int J Stroke. 2022;17:18–29. https://doi.org/10.1177/17474930211065917.CrossRefPubMed

Henderson SJ, Weitz JI, Kim PY. Fibrinolysis: strategies to enhance the treatment of acute ischemic stroke. J Thromb Haemost. 2018;16:1932–40. https://doi.org/10.1111/jth.14215.CrossRefPubMed

Jayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA. Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflamm. 2019;16:142. https://doi.org/10.1186/s12974-019-1516-2.CrossRef

Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med. 2011;17:796–808. https://doi.org/10.1038/nm.2399.CrossRefPubMedPubMedCentral

Perez-de-Puig I, et al. Neutrophil recruitment to the brain in mouse and human ischemic stroke. Acta Neuropathol. 2015;129:239–57. https://doi.org/10.1007/s00401-014-1381-0.CrossRefPubMed

Neumann J, et al. Beware the intruder: real time observation of infiltrated neutrophils and neutrophil-Microglia interaction during stroke in vivo. PLoS ONE. 2018;13: e0193970. https://doi.org/10.1371/journal.pone.0193970.CrossRefPubMedPubMedCentral

Sienel RI, Kataoka H, Kim SW, Seker FB, Plesnila N. Adhesion of leukocytes to cerebral venules precedes neuronal cell death and is sufficient to trigger tissue damage after cerebral ischemia. Front Neurol. 2021;12: 807658. https://doi.org/10.3389/fneur.2021.807658.CrossRefPubMed

El Amki M, et al. Neutrophils obstructing brain capillaries are a major cause of no-reflow in ischemic stroke. Cell Rep. 2020;33: 108260. https://doi.org/10.1016/j.celrep.2020.108260.CrossRefPubMed

Arumugam TV, et al. Contributions of LFA-1 and Mac-1 to brain injury and microvascular dysfunction induced by transient middle cerebral artery occlusion. Am J Physiol Heart Circ Physiol. 2004;287:H2555-2560. https://doi.org/10.1152/ajpheart.00588.2004.CrossRefPubMed

10.

Zhang L, et al. Effects of a selective CD11b/CD18 antagonist and recombinant human tissue plasminogen activator treatment alone and in combination in a rat embolic model of stroke. Stroke. 2003;34:1790–5. https://doi.org/10.1161/01.STR.0000077016.55891.2E.CrossRefPubMed

11.

Drieu A, Levard D, Vivien D, Rubio M. Anti-inflammatory treatments for stroke: from bench to bedside. Ther Adv Neurol Disord. 2018;11:1756286418789854. https://doi.org/10.1177/1756286418789854.CrossRefPubMedPubMedCentral

12.

Ghimire K, Altmann HM, Straub AC, Isenberg JS. Nitric oxide: what’s new to NO? Am J Physiol Cell Physiol. 2017;312:C254–62. https://doi.org/10.1152/ajpcell.00315.2016.CrossRefPubMed

13.

Cyr AR, Huckaby LV, Shiva SS, Zuckerbraun BS. Nitric oxide and endothelial dysfunction. Crit Care Clin. 2020;36:307–21. https://doi.org/10.1016/j.ccc.2019.12.009.CrossRefPubMedPubMedCentral

14.

Niwa M, Inao S, Takayasu M, Kawai T, Kajita Y, Nihashi T, Kabeya R, Sugimoto T, Yoshida J. Time course of expression of three nitric oxide synthase isoforms after transient middle cerebral artery occlusion in rats. Neurol Med Chir. 2001;41:63–73.CrossRef

15.

Angelis D, Savani R, Chalak L. Nitric oxide and the brain. Part 1: mechanisms of regulation, transport and effects on the developing brain. Pediatr Res. 2021;89:738–45. https://doi.org/10.1038/s41390-020-1017-0.CrossRefPubMed

16.

Bath PM, Krishnan K, Appleton JP. Nitric oxide donors (nitrates), L-arginine, or nitric oxide synthase inhibitors for acute stroke. Cochrane Database Syst Rev. 2017;4: CD000398. https://doi.org/10.1002/14651858.CD000398.pub2.CrossRefPubMed

17.

Terpolilli NA, et al. Inhalation of nitric oxide prevents ischemic brain damage in experimental stroke by selective dilatation of collateral arterioles. Circ Res. 2012;110:727–38. https://doi.org/10.1161/CIRCRESAHA.111.253419.CrossRefPubMed

18.

Fox-Robichaud A, Payne D, Hasan SU, Ostrovsky L, Fairhead T, Reinhardt P, Kubes P. Inhaled NO as a viable antiadhesive therapy for ischemia/reperfusion injury of distal microvascular beds. J Clin Invest. 1998;101:2497.CrossRefPubMedPubMedCentral

19.

Nagasaka Y, et al. Pharmacological preconditioning with inhaled nitric oxide (NO): organ-specific differences in the lifetime of blood and tissue NO metabolites. Nitric Oxide. 2018;80:52–60. https://doi.org/10.1016/j.niox.2018.08.006.CrossRefPubMedPubMedCentral

20.

Lundberg JO, Weitzberg E. NO generation from nitrite and its role in vascular control. Arterioscler Thromb Vasc Biol. 2005;25:915–22. https://doi.org/10.1161/01.ATV.0000161048.72004.c2.CrossRefPubMed

21.

Malone K, Amu S, Moore AC, Waeber C. The immune system and stroke: from current targets to future therapy. Immunol Cell Biol. 2019;97:5–16. https://doi.org/10.1111/imcb.12191.CrossRefPubMed

22.

Zhang S, et al. Rationale and design of combination of an immune modulator fingolimod with alteplase bridging with mechanical thrombectomy in acute ischemic stroke (FAMTAIS) trial. Int J Stroke. 2017;12:906–9. https://doi.org/10.1177/1747493017710340.CrossRefPubMed

23.

Fung C, et al. Inhaled nitric oxide treatment for aneurysmal SAH patients with delayed cerebral ischemia. Front Neurol. 2022;13: 817072. https://doi.org/10.3389/fneur.2022.817072.CrossRefPubMedPubMedCentral

24.

Terpolilli NA, et al. Nitric oxide inhalation reduces brain damage, prevents mortality, and improves neurological outcome after subarachnoid hemorrhage by resolving early pial microvasospasms. J Cereb Blood Flow Metab. 2016;36:2096–107. https://doi.org/10.1177/0271678x15605848.CrossRefPubMed

25.

Liu K, Li Q, Zhang L, Zheng X. The dynamic detection of NO during stroke and reperfusion in vivo. Brain Inj. 2009;23:450–8. https://doi.org/10.1080/02699050902838173.CrossRefPubMed

26.

Kuebler WM, et al. Inhaled nitric oxide induces cerebrovascular effects in anesthetized pigs. Neurosci Lett. 2003;348:85–8. https://doi.org/10.1016/s0304-3940(03)00722-5.CrossRefPubMed

27.

Khan MF, Azfar MF, Khurshid SM. The role of inhaled nitric oxide beyond ARDS. Indian J Crit Care Med. 2014;18:392–5. https://doi.org/10.4103/0972-5229.133931.CrossRefPubMedPubMedCentral

28.

Papadimos TJ, Medhkour A, Yermal S. Successful use of inhaled nitric oxide to decrease intracranial pressure in a patient with severe traumatic brain injury complicated by acute respiratory distress syndrome: a role for an anti-inflammatory mechanism? Scand J Trauma Resusc Emerg Med. 2009;17:5. https://doi.org/10.1186/1757-7241-17-5.CrossRefPubMedPubMedCentral

29.

Pastor P, Curvello V, Hekierski H, Armstead WM. Inhaled nitric oxide protects cerebral autoregulation through prevention of impairment of ATP and calcium sensitive K channel mediated cerebrovasodilation after traumatic brain injury. Brain Res. 2019;1711:1–6. https://doi.org/10.1016/j.brainres.2019.01.008.CrossRefPubMed

30.

Gianetti J, et al. Supplemental nitric oxide and its effect on myocardial injury and function in patients undergoing cardiac surgery with extracorporeal circulation. J Thorac Cardiovasc Surg. 2004;127:44–50. https://doi.org/10.1016/j.jtcvs.2002.08.001.CrossRefPubMed

31.

Lang JD Jr, et al. Inhaled NO accelerates restoration of liver function in adults following orthotopic liver transplantation. J Clin Invest. 2007;117:2583–91. https://doi.org/10.1172/JCI31892.CrossRefPubMedPubMedCentral

32.

Hataishi R, et al. Inhaled nitric oxide decreases infarction size and improves left ventricular function in a murine model of myocardial ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol. 2006;291:H379-384. https://doi.org/10.1152/ajpheart.01172.2005.CrossRefPubMed

33.

Inglessis I, et al. Hemodynamic effects of inhaled nitric oxide in right ventricular myocardial infarction and cardiogenic shock. J Am Coll Cardiol. 2004;44:793–8. https://doi.org/10.1016/j.jacc.2004.05.047.CrossRefPubMed

34.

Frostell C, Fratacci MD, Wain JC, Jones R, Zapol WM. Inhaled nitric oxide. A selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction. Circulation. 1991;83:2038–47. https://doi.org/10.1161/01.cir.83.6.2038.CrossRefPubMed

35.

Krejcy K, et al. Role of nitric oxide in hemostatic system activation in vivo in humans. Arterioscler Thromb Vasc Biol. 1995;15:2063–7. https://doi.org/10.1161/01.atv.15.11.2063.CrossRefPubMed

36.

Waldow T, Witt W, Weber E, Matschke K. Nitric oxide donor-induced persistent inhibition of cell adhesion protein expression and NFkappaB activation in endothelial cells. Nitric Oxide. 2006;15:103–13. https://doi.org/10.1016/j.niox.2005.12.005.CrossRefPubMed

37.

Carreau A, Kieda C, Grillon C. Nitric oxide modulates the expression of endothelial cell adhesion molecules involved in angiogenesis and leukocyte recruitment. Exp Cell Res. 2011;317:29–41. https://doi.org/10.1016/j.yexcr.2010.08.011.CrossRefPubMed

38.

De Caterina R, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest. 1995;96:60–8. https://doi.org/10.1172/jci118074.CrossRefPubMedPubMedCentral

39.

Jiang MZ, et al. Effects of antioxidants and NO on TNF-alpha-induced adhesion molecule expression in human pulmonary microvascular endothelial cells. Respir Med. 2005;99:580–91. https://doi.org/10.1016/j.rmed.2004.10.007.CrossRefPubMed

40.

Lo HP, Ackland-Berglund CE, Pritchard KA Jr, Guice KS, Oldham KT. Attenuated expression of inducible nitric oxide synthase in lung microvascular endothelial cells is associated with an increase in ICAM-1 expression. J Pediatr Surg. 2001;36:1136–42. https://doi.org/10.1053/jpsu.2001.25731.CrossRefPubMed

41.

Liu P, et al. NO modulates P-selectin and ICAM-1 mRNA expression and hemodynamic alterations in hepatic I/R. Am J Physiol. 1998;275:H2191-2198. https://doi.org/10.1152/ajpheart.1998.275.6.H2191.CrossRefPubMed

42.

Ahluwalia A, et al. Antiinflammatory activity of soluble guanylate cyclase: cGMP-dependent down-regulation of P-selectin expression and leukocyte recruitment. Proc Natl Acad Sci U S A. 2004;101:1386–91. https://doi.org/10.1073/pnas.0304264101.CrossRefPubMedPubMedCentral

43.

Mathru M, Huda R, Solanki DR, Hays S, Lang JD. Inhaled nitric oxide attenuates reperfusion inflammatory responses in humans. Anesthesiology. 2007;106:275–82. https://doi.org/10.1097/00000542-200702000-00015.CrossRefPubMed

44.

Banick PD, Chen Q, Xu YA, Thom SR. Nitric oxide inhibits neutrophil beta 2 integrin function by inhibiting membrane-associated cyclic GMP synthesis. J Cell Physiol. 1997;172:12–24. https://doi.org/10.1002/(sici)1097-4652(199707)172:1%3c12::Aid-jcp2%3e3.0.Co;2-g.CrossRefPubMed

45.

Bhopale VM, Yang M, Yu K, Thom SR. Factors associated with nitric oxide-mediated β2 integrin inhibition of neutrophils. J Biol Chem. 2015;290:17474–84. https://doi.org/10.1074/jbc.M115.651620.CrossRefPubMedPubMedCentral

46.

Thom SR, et al. Nitric-oxide synthase-2 linkage to focal adhesion kinase in neutrophils influences enzyme activity and β2 integrin function. J Biol Chem. 2013;288:4810–8. https://doi.org/10.1074/jbc.M112.426353.CrossRefPubMedPubMedCentral

47.

Giustizieri ML, Albanesi C, Scarponi C, De Pità O, Girolomoni G. Nitric oxide donors suppress chemokine production by keratinocytes in vitro and in vivo. Am J Pathol. 2002;161:1409–18. https://doi.org/10.1016/s0002-9440(10)64416-1.CrossRefPubMedPubMedCentral

48.

Pawluk H, et al. The role of selected pro-inflammatory cytokines in pathogenesis of ischemic stroke. Clin Interv Aging. 2020;15:469–84. https://doi.org/10.2147/CIA.S233909.CrossRefPubMedPubMedCentral

49.

Zhu H, et al. Interleukins and ischemic stroke. Front Immunol. 2022;13: 828447. https://doi.org/10.3389/fimmu.2022.828447.CrossRefPubMedPubMedCentral

50.

Clausen BH, et al. Characterization of the TNF and IL-1 systems in human brain and blood after ischemic stroke. Acta Neuropathol Commun. 2020;8:81. https://doi.org/10.1186/s40478-020-00957-y.CrossRefPubMedPubMedCentral

51.

Emsley HC, et al. Clinical outcome following acute ischaemic stroke relates to both activation and autoregulatory inhibition of cytokine production. BMC Neurol. 2007;7:5. https://doi.org/10.1186/1471-2377-7-5.CrossRefPubMedPubMedCentral

52.

Jickling GC, Sharp FR. Blood biomarkers of ischemic stroke. Neurotherapeutics. 2011;8:349–60. https://doi.org/10.1007/s13311-011-0050-4.CrossRefPubMedPubMedCentral

53.

Tsao PS, McEvoy LM, Drexler H, Butcher EC, Cooke JP. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine. Circulation. 1994;89:2176–82. https://doi.org/10.1161/01.cir.89.5.2176.CrossRefPubMed

54.

Ma XL, Weyrich AS, Lefer DJ, Lefer AM. Diminished basal nitric oxide release after myocardial ischemia and reperfusion promotes neutrophil adherence to coronary endothelium. Circ Res. 1993;72:403–12. https://doi.org/10.1161/01.res.72.2.403.CrossRefPubMed

55.

Kubes P, Suzuki M, Granger DN. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci U S A. 1991;88:4651–5. https://doi.org/10.1073/pnas.88.11.4651.CrossRefPubMedPubMedCentral

56.

Vovenko EP, Chuikin AE. Tissue oxygen tension profiles close to brain arterioles and venules in the rat cerebral cortex during the development of acute anemia. Neurosci Behav Physiol. 2010;40:723–31. https://doi.org/10.1007/s11055-010-9318-0.CrossRefPubMed

57.

McMahon TJ, Doctor A. Extrapulmonary effects of inhaled nitric oxide: role of reversible S-nitrosylation of erythrocytic hemoglobin. Proc Am Thorac Soc. 2006;3:153–60. https://doi.org/10.1513/pats.200507-066BG.CrossRefPubMedPubMedCentral

58.

Cannon RO, et al. Effects of inhaled nitric oxide on regional blood flow are consistent with intravascular nitric oxidedelivery. J Clin Investig. 2001;108:279–87. https://doi.org/10.1172/jci200112761.CrossRefPubMedPubMedCentral

59.

Li H, Samouilov A, Liu X, Zweier JL. Characterization of the magnitude and kinetics of xanthine oxidase-catalyzed nitrate reduction: evaluation of its role in nitrite and nitric oxide generation in anoxic tissues. Biochemistry. 2003;42:1150–9. https://doi.org/10.1021/bi026385a.CrossRefPubMed

60.

Webb AJ, et al. Mechanisms underlying erythrocyte and endothelial nitrite reduction to nitric oxide in hypoxia: role for xanthine oxidoreductase and endothelial nitric oxide synthase. Circ Res. 2008;103:957–64. https://doi.org/10.1161/CIRCRESAHA.108.175810.CrossRefPubMedPubMedCentral

61.

Moncada S, Bolanos JP. Nitric oxide, cell bioenergetics and neurodegeneration. J Neurochem. 2006;97:1676–89. https://doi.org/10.1111/j.1471-4159.2006.03988.x.CrossRefPubMed

62.

Kapil V, et al. The noncanonical pathway for in vivo nitric oxide generation: the nitrate-nitrite-nitric oxide pathway. Pharmacol Rev. 2020;72:692–766. https://doi.org/10.1124/pr.120.019240.CrossRefPubMed

63.

Atochin DN, et al. Soluble guanylate cyclase alpha1beta1 limits stroke size and attenuates neurological injury. Stroke. 2010;41:1815–9. https://doi.org/10.1161/STROKEAHA.109.577635.CrossRefPubMedPubMedCentral

64.

Langhauser F, et al. A diseasome cluster-based drug repurposing of soluble guanylate cyclase activators from smooth muscle relaxation to direct neuroprotection. NPJ Syst Biol Appl. 2018;4:8. https://doi.org/10.1038/s41540-017-0039-7.CrossRefPubMedPubMedCentral

65.

Zhang Q, et al. Functional relevance of Golgi- and plasma membrane-localized endothelial NO synthase in reconstituted endothelial cells. Arterioscler Thromb Vasc Biol. 2006;26:1015–21. https://doi.org/10.1161/01.ATV.0000216044.49494.c4.CrossRefPubMed

66.

Sánchez FA, et al. Functional significance of differential eNOS translocation. Am J Physiol Heart Circ Physiol. 2006;291:H1058-1064. https://doi.org/10.1152/ajpheart.00370.2006.CrossRefPubMed

67.

Marín N, et al. S-Nitrosation of β-catenin and p120 catenin: a novel regulatory mechanism in endothelial hyperpermeability. Circ Res. 2012;111:553–63. https://doi.org/10.1161/circresaha.112.274548.CrossRefPubMedPubMedCentral

68.

Swirski FK, et al. Identification of splenic reservoir monocytes and their deployment to inflammatory sites. Science. 2009;325:612–6. https://doi.org/10.1126/science.1175202.CrossRefPubMedPubMedCentral

69.

Khambata RS, et al. Antiinflammatory actions of inorganic nitrate stabilize the atherosclerotic plaque. Proc Natl Acad Sci U S A. 2017;114:E550–9. https://doi.org/10.1073/pnas.1613063114.CrossRefPubMedPubMedCentral

70.

Ghosh SM, et al. Enhanced vasodilator activity of nitrite in hypertension: critical role for erythrocytic xanthine oxidoreductase and translational potential. Hypertension. 2013;61:1091–102. https://doi.org/10.1161/hypertensionaha.111.00933.CrossRefPubMed

Title: Inhaled nitric oxide suppresses neuroinflammation in experimental ischemic stroke
Authors: Rebecca I. Sienel
Uta Mamrak
Janina Biller
Stefan Roth
Andreas Zellner
Tipparat Parakaw
Rayomand S. Khambata
Arthur Liesz
Christof Haffner
Amrita Ahluwalia
Burcu F. Seker
Nikolaus Plesnila
Publication date: 01-12-2023
Publisher: BioMed Central
Keywords: Stroke
Nitrate
Published in: Journal of Neuroinflammation / Issue 1/2023
Electronic ISSN: 1742-2094
DOI: https://doi.org/10.1186/s12974-023-02988-3

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Inhaled nitric oxide suppresses neuroinflammation in experimental ischemic stroke

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Abstract

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