Role of Cellular Senescence and NOX4-Mediated Oxidative Stress in Systemic Sclerosis Pathogenesis

Current Rheumatology Reports

Volumn 17, Issue 1, 2015, Pages

  Piera Velazquez, Sonsoles ^a,b   Jimenez, Sergio A ^a,b  

^a THOMAS JEFFERSON UNIVERSITY   (United States)

^b THOMAS JEFFERSON UNIVERSITY   (United States)

Author keywords

Cellular senescence; Fibrosis; NOX4; Oxidative stress; ROS; Systemic sclerosis

Indexed keywords

CAVEOLIN 1; PHOSPHATIDYLINOSITOL 3,4,5 TRISPHOSPHATE 3 PHOSPHATASE; REACTIVE OXYGEN METABOLITE; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 1; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 2; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE 4; SMAD PROTEIN; TELOMERASE; TRANSFORMING GROWTH FACTOR BETA RECEPTOR; NOX4 PROTEIN, HUMAN; REDUCED NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE;

ARTICLE; AUTOPHAGY; BONE MARROW DERIVED MESENCHYMAL STEM CELL; CELL AGING; CELL DIFFERENTIATION; ENZYME ACTIVITY; FIBROBLAST; HUMAN; NONHUMAN; OXIDATIVE STRESS; PATHOGENESIS; PROTEIN EXPRESSION; PROTEIN PROTEIN INTERACTION; SIGNAL TRANSDUCTION; SYSTEMIC SCLEROSIS; TELOMERE SHORTENING; UPREGULATION; FIBROSIS; METABOLISM; PATHOLOGY; PATHOPHYSIOLOGY; PHYSIOLOGY;

CELL AGING; FIBROSIS; HUMANS; NADPH OXIDASE; OXIDATIVE STRESS; REACTIVE OXYGEN SPECIES; SCLERODERMA, SYSTEMIC;

EID: 84919904439     PISSN: 15233774     EISSN: 15346307     Source Type: Journal    
DOI: 10.1007/s11926-014-0473-0     Document Type: Article

References (132)

1. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009;360:1989–2003.
2. Matucci-Cerinic M, Kahaleh B, Wigley FM. Review: evidence that systemic sclerosis is a vascular disease. Arthritis Rheum. 2013;65:1953–62.
3. Elhai M, Meune C, Avouac J, Kahan A, Allanore Y. Trends in mortality in patients with systemic sclerosis over 40 years: a systematic review and meta-analysis of cohort studies. Rheumatology (Oxford). 2012;51:1017–26.
4. Eckes B, Moinzadeh P, Sengle G, Hunzelmann N, Krieg T. Molecular and cellular basis of scleroderma. J Mol Med (Berl). 2014;92:913–24.
5. Katsumoto TR, Whitfield ML, Connolly MK. The pathogenesis of systemic sclerosis. Annu Rev Pathol. 2011;6:509–37.
6. Bhattacharyya S, Wei J, Varga J. Understanding fibrosis in systemic sclerosis: shifting paradigms, emerging opportunities. Nat Rev Rheumatol. 2011;25:42–54.
7. Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clin Invest. 2007;117:557–67.
8. Mayes MD, Lacey Jr JV, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48:2246–55.
9. Hayflick L, Moorehead PS. The serial cultivation of human diploid cell strains. Exp Cell Res. 1961;25:585–621.
10. Hayflick L. The limited in vitro lifetime of human diploid cell strains. Exp Cell Res. 1965;37:614–36.
11. van Deursen JM. The role of senescence cells in ageing. Nature. 2014;509:439–46.
12. Salama R, Sadaie M, Hoare M, Narita M. Cellular senescence and its effector programs. Genes Dev. 2014;28:99–114.
13. Muñoz-Espin D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014;15:482–96.
14. Sikora E, Arendt T, Bennett M, Narita M. Impact of cellular senescence signature on ageing research. Ageing Res Rev. 2011;10:146–52.
15. Erol A. Deciphering the intricate regulatory mechanisms for the cellular choice between cell repair, apoptosis or senescence in response to damaging signals. Cell Signal. 2011;23:1076–81.
16. Ben-Porath I, Weinberg RA. The signals and pathways activating cellular senescence. Int J Biochem Cell Biol. 2005;37:961–76.
17. Campisi J, Anderson JK, Kapahi P, Melov S. Cellular senescence: a link between cancer and age-related degenerative disease? Semin Cancer Biol. 2011;21:354–9. Review of the studies that lead to the identification of the “Senescence Associated Secretory Phenotype”.
18. Tchkonia T, Zhu Y, van Deursen J, Campisi J, Kirkland JL. Cellular senescence and the senescent secretory phenotype: therapeutic opportunities. J Clin Invest. 2013;123:966–72.
19. Freund A, Orjalo AV, Desprez PY, Campisi J. Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med. 2010;16:238–46.
20. Coppe JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99–118.
21. Salminen A, Kauppinen A, Kaarniranta K. Emerging role of NF-kB signaling in the induction of senescence-associated secretory phenotype (SASP). Cell Signal. 2012;24:835–45.
22. Muñoz-Espin D, Canamero M, Maraver A, Gomez-Lopez G, Contreras J, Murillo-Cuesta S, et al. Programmed cell senescence during mammalian embryonic development. Cell. 2013;155:1104–18.
23. Storer M, Mas A, Robert-Moreno A, Pecoraro M, Ortells MC, Di Giacomo V, et al. Senescence is a developmental mechanism that contributes to embryonic growth and patterning. Cell. 2013;155:1119–30. Refs. 22 and 23 describe elegant studies identifying the role of cellular senescence during embryonic growth and development.
24. Chen JH, Hales CN, Ozanne SE. DNA damage, cellular senescence and organismal ageing: casual or correlative? Nucleic Acids Res. 2007;35:7417–28.
25. Collado M, Blasco MA, Serrano M. Cellular senescence in cancer and aging. Cell. 2007;130:223–33.
26. Gorgoulis VG, Halazonetis TD. Oncogene induced senescence: the bright and dark side of the response. Curr Opin Cell Biol. 2010;22:816–27.
27. Kuilman T, Michaloglou C, Mooi WJ, Peeper DS. The essence of senescence. Genes Dev. 2010;24:2463–79.
28. Harley CB, Futcher AB, Greider CW. Telomeres shorten during ageing of human fibroblasts. Nature. 1990;354:458–60.
29. Chen Q, Fischer A, Reagan JD, Yan LJ, Ames BN. Oxidative DNA damage and senescence of human diploid fibroblast cells. Proc Natl Acad Sci U S A. 1995;92:4337–41.
30. Chen QM. Replicative senescence and oxidant-induced premature senescence. Beyond the control of cell cycle checkpoints. Ann N Y Acad Sci. 2000;908:111–25.
31. Parrinello S, Samper E, Krtolica A, Goldstein J, Melov S, Campisi J. Oxygen sensitivity severely limits the replicative lifespan of murine fibroblasts. Nat Cell Biol. 2003;5:741–7.
32. Passos JF, Simillion C, Hallinan J, Wipat A, von Zglinicki T. Cellular senescence: unraveling complexity. Age (Dordrecht). 2009;31:353–63.
33. Muller M. Cellular senescence: molecular mechanisms, in vivo significance, and redox considerations. Antioxid Redox Signal. 2009;11:59–98.
34. Passos JF, Nelson G, Wang C, Richter T, Simillion C, Proctor CJ, et al. Feedback between p21 and reactive oxygen production is necessary for cell senescence. Mol Syst Biol. 2010;6:347.
35. Kim TK, Lee JS, Jung JE, Oh SY, Kwak S, Jin X, et al. Interferon regulatory factor 3 activates p53-dependent cell growth inhibition. Cancer Lett. 2006;242:215–21.
36. Song LL, Alimirah F, Panchanathan R, Xin H, Choubey D. Expression of an IFN-inducible cellular senescence gene, IFI16, is up-regulated by p53. Mol Cancer Res. 2008;6:1732–41.
37. Duan X, Ponomareva L, Veeranki S, Panchanathan R, Dickerson E, Choubey D. Differential roles for the interferon-inducible IFI16 and AIM2 innate immune sensors for cystosolic DNA in cellular senescence of human fibroblasts. Mol Cancer Res. 2011;9:589–602.
38. Dumit VI, Kuttner V, Kappler J, Piera-Velazquez S, Jimenez SA, Bruckner-Tuderman L, et al. Altered MCM protein levels and autophagic flux in aged and systemic sclerosis dermal fibroblasts. J Invest Dermatol. 2014;134:2321–30. Novel study demonstrating the occurrence of cellular senescence-associated changes in Systemic Sclerosis dermal fibroblast cell lines employing proteomics.
39. Cipriani P, Guiducci S, Miniati I, Cinelli M, Urbani S, Marrelli A, et al. Impairment of endothelial cell differentiation from bone marrow-derived mesenchymal stem cells: new insight into the pathogenesis of systemic sclerosis. Arthritis Rheum. 2007;56:1994–2004.
40. Goronzy J, Fujii H, Weyand CM. Telomeres, immune aging, and autoimmunity. Exp Gerontol. 2006;41:246–51.
41. Debbi AZ, Radstake TRDJ, Broen JCA. Accelerated telomere shortening in rheumatic diseases: cause or consequence? Expert Rev Clin Immunol. 2013;9:1193–204.
42. Arlett CM, Black CM, Briggs DC, Stevens CO, Welsh KI. Telomere reduction in scleroderma patients: a possible cause for chromosomal instability. Br J Rheumatol. 1996;35:732–7.
43. Ohtsuka T. Life span of skin fibroblasts in patients with systemic sclerosis. Dermatology. 1998;196:204–7.
44. MacIntyre A, Brouilette SW, Lamb K, Radhakrishnan K, McGlynn L, Chee MM, et al. Association of increased telomere lengths in limited scleroderma, with a lack of age-related telomere erosion. Ann Rheum Dis. 2008;67:1780–2.
45. Tarhan F, Vural F, Kosova B, Aksu K, Cogulu O, Keser G. Telomerase activity in connective tissue diseases: elevated in rheumatoid arthritis, but markedly decreased in systemic sclerosis. Rheumatol Int. 2008;28:579–83.
46. Thannickal VJ. Mechanistic links between aging and lung fibrosis. Biogerontology. 2013;14:609–15.
47. Chilosi M, Carloni A, Rossi A, Poletti V. Premature lung aging and cellular senescence in the pathogenesis of idiopathic pulmonary fibrosis and COPD/emphysema. Transl Res. 2013;162:156–73.
48. Steele MP, Schwartz DA. Molecular mechanisms in progressive idiopathic pulmonary fibrosis. Annu Rev Med. 2013;64:265–76.
49. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356:1317–26.
50. Diazdeleon A, Cronkhite JT, Katzenstein AL, Godwin JD, Raghu G, Glazer CS, et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations. PLoS One. 2010;5:e10680. doi:10.1371/journal.pone.0010680.
51. Del Galdo F, Sotgia F, de Almeida CJ, Jasmin JF, Musick M, Lisanti MP, et al. Decreased expression of caveolin 1 in patients with systemic sclerosis: crucial role in the pathogenesis of tissue fibrosis. Arthritis Rheum. 2008;58:2854–65.
52. Del Galdo F, Lisanti MP, Jimenez SA. Caveolin-1, transforming growth factor-beta receptor internalization, and the pathogenesis of systemic sclerosis. Curr Opin Rheumatol. 2008;20:713–9.
53. Wang XM, Zhang Y, Kim HP, Zhou Z, Feghali-Bostwick CA, Liu F, et al. Caveolin-1: a critical regulator of lung fibrosis in idiopathic pulmonary fibrosis. J Exp Med. 2006;203:2895–906.
54. Tourkina E, Richard M, Gööz P, Bonner M, Pannu J, Harley R, et al. Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol. 2008;294:L843–61.
55. Gvaramia D, Blaauboer ME, Hanemaaijer R, Everts V. Role of caveolin-1 in fibrotic diseases. Matrix Biol. 2013;32:307–15. Comprehensive review of the extensive published evidence demonstrating the crucial role of caveolin-1 in the pathogenesis of various fibrotic diseases including Systemic Sclerosis.
56. Volonte D, Zhang K, Lisanti MP, Galbiati F. Expression of caveolin-1 induces premature cellular senescence in primary cultures of murine fibroblasts. Mol Biol Cell. 2002;13:2502–17.
57. Shivshankar P, Brampton C, Miyasato S, Kasper M, Thannickal VJ, Le Saux CJ. Caveolin-1 deficiency protects from pulmonary fibrosis by modulating epithelial cell senescence in mice. Am J Respir Cell Mol Biol. 2012;47:28–36.
58. Xia H, Khalil W, Kahm J, Jessurun J, Kleidon J, Henke CA. Pathologic caveolin-1 regulation of PTEN in idiopathic pulmonary fibrosis. Am J Pathol. 2010;176:2626–37.
59. Parapuram SK, Shi-wen X, Elliott C, Welch ID, Jones H, Baron M, et al. Loss of PTEN expression by dermal fibroblasts causes fibrosis. J Invest Dermatol. 2011;131:1996–2003.
60. Murrell DF. A radical proposal for the pathogenesis of scleroderma. J Am Acad Dermatol. 1993;28:78–85.
61. Gabrielli A, Svegliati S, Moroncini G, Pomponio G, Santillo M, Avvedimento EV. Oxidative stress and the pathogenesis of scleroderma: the Murrell’s hypothesis revisited. Semin Immunopathol. 2008;30:329–37.
62. Piera-Velazquez S, Jimenez SA. Role of oxidative stress and reactive oxygen radicals in the pathogenesis of systemic sclerosis. In: MJ Alcaraz, editors. Studies on arthritis and joint disorders, oxidative stress in applied basic research and clinical practice. doi:10.1007/978-1-4614-6166-1_10.pp.183-197.
63. Gabrielli A, Svegliati S, Moroncini G, Amico D. New insights into the role of oxidative stress in scleroderma fibrosis. Open Rheumatol J. 2012;6:87–95.
64. Ogawa F, Shimizu K, Muroi E, Hara T, Sato S. Increasing levels of serum antioxidant status, total antioxidant power, in systemic sclerosis. Clin Rheumatol. 2011;30:921–5. This study measured the total antioxidant power in serum from SSc patients and found that approximately one-quarter of these patients had elevated levels although there were no differences between patients with the diffuse or limited SSc subsets.
65. Savas E, Aksoy N, Pehlivan Y, Sayiner ZA, Oztürk ZA, Tabur S, et al. Evaluation of oxidant and antioxidant status and relation with prolidase in systemic sclerosis. Wien Klin Wochenschr. 2014;126:341–6. This interesting study demonstrated that the “total oxidant status” and the “oxidative stress index” were higher in Systemic Sclerosis patients than in healthy controls whereas there were no differences in “total antioxidant status”.
66. Sambo P, Jannino L, Candela M, Salvi A, Donini M, Dusi S, et al. Monocytes of patients with systemic sclerosis (scleroderma) spontaneously release in vitro increased amounts of superoxide anion. J Invest Dermatol. 1999;112:78–84.
67. Allanore Y, Borderie D, Lemarechal H, Ekindjian OG, Kahan A. Acute and sustained effects of dihydropyridine-type calcium channel antagonists on oxidative stress in systemic sclerosis. Am J Med. 2004;116:595–600.
68. Servettaz A, Guilpain P, Goulvestre C, Chereau C, Hercend C, Nicco C, et al. Radical oxygen species production induced by advanced oxidation protein products predicts clinical evolution and response to treatment in systemic sclerosis. Ann Rheum Dis. 2007;66:1202–9.
69. Sambo P, Baroni SS, Luchetti M, Paroncini P, Dusi S, Orlandini S, et al. Oxidative stress in scleroderma: maintenance of scleroderma fibroblast phenotype by the constitutive up-regulation of reactive oxygen species generation through the NADPH oxidase complex pathway. Arthritis Rheum. 2001;44:2653–64.
70. Avouac J, Borderie D, Ekindjian OG, Kahan A, Allanore Y. High DNA oxidative damage in systemic sclerosis. J Rheumatol. 2010;37:2540–7.
71. Stein CM, Tanner SB, Awad JA, Roberts II LJ, Morrow JD. Evidence of free radical-mediated injury (isoprostane overproduction) in scleroderma. Arthritis Rheum. 1996;39:1146–50.
72. Ogawa F, Shimizu K, Muroi E, Hara T, Hasegawa M, Takehara K, et al. Serum levels of 8-isoprostane, a marker of oxidative stress, are elevated in patients with systemic sclerosis. Rheumatology (Oxford). 2006;45:815–8.
73. Cracowski JL, Marpeau C, Carpentier PH, Imbert B, Hunt M, Stanke-Labesque F, et al. Enhanced in vivo lipid peroxidation in scleroderma spectrum disorders. Arthritis Rheum. 2001;44:1143–8.
74. Volpe A, Biasi D, Caramaschi P, Mantovani W, Bambara LM, Canestrini S, et al. Levels of F2-isoprostanes in systemic sclerosis: correlation with clinical features. Rheumatology (Oxford). 2006;45:314–20.
75. Tufvesson E, Bozovic G, Hesselstrand R, Bjermer L, Scheja A, Wuttge DM. Increased cysteinyl-leukotrienes and 8-isoprostane in exhaled breath condensate from systemic sclerosis patients. Rheumatology (Oxford). 2010;49:2322–6.
76. Morrow JD. The isoprostanes: their quantification as an index of oxidant stress status in vivo. Drug Metab Rev. 2000;32:377–85.
77. Shimizu K, Ogawa F, Akiyama Y, Muroi E, Yoshizaki A, Iwata Y, et al. Increased serum levels of N(epsilon)-(hexanoyl)lysine, a new marker of oxidative stress, in systemic sclerosis. J Rheumatol. 2008;35:2214–9.
78. Ogawa F, Shimizu K, Hara T, Muroi E, Hasegawa M, Takehara K, et al. Serum levels of heat shock protein 70, a biomarker of cellular stress, are elevated in patients with systemic sclerosis: association with fibrosis and vascular damage. Clin Exp Rheumatol. 2008;26:659–62.
79. Boin F, Erre GL, Posadino AM, Cossu A, Giordo R, Spinetti G, et al. Oxidative stress-dependent activation of collagen synthesis is induced in human pulmonary smooth muscle cells by sera from patients with scleroderma-associated pulmonary hypertension. Orphanet J Rare Dis. 2014;9:123.
80. Holmström KM, Finkel T. Cellular mechanisms and physiological consequences of redox-dependent signalling. Nat Rev Mol Cell Biol. 2014;15:411–21.
81. Schieber M, Chandel NS. ROS function in redox signaling and oxidative stress. Curr Biol. 2014;24:R453–62.
82. Finkel T. Signal transduction by reactive oxygen species. J Cell Biol. 2011;194:7–15.
83. Svegliati S, Marrone G, Pezone A, Spadoni T, Grieco A, Moroncini G, et al. Oxidative DNA damage induces the ATM-mediated transcriptional suppression of the Wnt inhibitor WIF-1 in systemic sclerosis and fibrosis. Sci Signal. 2014;7(341):ra84. doi:10.1126/scisignal.2004592. Extensive study that ties together ROS-mediated oxidative stress, DNA damage and activation of the Wnt fibrotic pathway caused by ROS-induced loss of the anti-Wnt protein, Wnt inhibitory factor 1 (WIF-1).
84. Dooley A, Shi-Wen X, Aden N, Tranah T, Desai N, Denton CP. Modulation of collagen type I, fibronectin and dermal fibroblast function and activity, in systemic sclerosis by the antioxidant epigallocatechin-3-gallate. Rheumatology (Oxford). 2010;49:2024–36. Highly provocative study demonstrating modulation of the profibrotic phenotype of Systemic Sclerosis dermal fibroblasts by the antioxidant epigallocatechin-3-gallate.
85. Tsou PS, Talia NN, Pinney AJ, Kendzicky A, Piera-Velazquez S, Jimenez SA, et al. Effect of oxidative stress on protein tyrosine phosphatase 1B in scleroderma dermal fibroblasts. Arthritis Rheum. 2012;64:1978–89. Pioneering study exploring the role of PTP1B in the regulation of the fibrotic process in SSc demonstrating that PTP1B activity was substantially reduced in SSc dermal fibroblasts as a result of increased ROS-induced cysteine residue oxidation in the protein.
86. Kawahara T, Quinn MT, Lambeth JD. Molecular evolution of the reactive oxygen-generating NADPH oxidase (Nox/Duox) family of enzymes. BMC Evol Biol. 2007;7:109.
87. Sumimoto H. Structure, regulation and evolution of Nox-family NADPH oxidases that produce reactive oxygen species. FEBS J. 2008;275:3249–77.
88. Lambeth JD, Neish AS. Nox enzymes and new thinking on reactive oxygen: a double-edged sword revisited. Annu Rev Pathol. 2014;9:119–45.
89. Bedard K, Krause KH. The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiol Rev. 2007;87:245–313.
90. Geiszt M. NADPH oxidases: new kids on the block. Cardiovasc Res. 2006;71:289–99.
91. Cucoranu I, Clempus R, Dikalova A, et al. NAD(P)H oxidase 4 mediates transforming growth factor-beta1-induced differentiation of cardiac fibroblasts into myofibroblasts. Circ Res. 2005;97:900–7.
92. Sturrock A, Cahill B, Norman K, Huecksteadt TP, Hill K, Sanders K, et al. Transforming growth factor-beta1 induces Nox4 NAD(P)H oxidase and reactive oxygen species-dependent proliferation in human pulmonary artery smooth muscle cells. Am J Physiol Lung Cell Moll Physiol. 2006;290:L661–73.
93. Hecker L, Vittal R, Jones T, et al. NADPH oxidase-4 mediates myofibroblast activation and fibrogenic responses to lung injury. Nat Med. 2009;15:1077–81.
94. Datla SR, Peshavariya H, Dusting GJ, Mahadev K, Goldstein BJ, Jiang F. Important role of Nox4 type NADPH oxidase in angiogenic responses in human microvascular endothelial cells in vitro. Arterioscler Thromb Vasc Biol. 2007;27:2319–24.
95. An SJ, Boyd R, Zhu M, Chapman A, Pimentel DR, Wang HD. NADPH oxidase mediates angiotensin II-induced endothelin-1 expression in vascular adventitial fibroblasts. Cardiovasc Res. 2007;75:702–9.
96. Duerrschmidt N, Wippich N, Goettsch W, Broemme HJ, Morawietz H. Endothelin-1 induces NAD(P)H oxidase in human endothelial cells. Biochem Biophys Res Commun. 2000;269:713–7.
97. Manickam N, Patel M, Griendling KK, Gorin Y, Barnes JL. RhoA/Rho kinase mediate TGF-β1-induced kidney myofibroblast activation through Poldip2/NOX4-derived reactive oxygen species. Am J Physiol Renal Physiol. 2014;307:F159–71.
98. Bondi CD, Manickham N, Lee DY, Block K, Gorin Y, Abboud HE, et al. NAD(P)H oxidase mediates TGF-beta1-induced activation of kidney myofibroblasts. J Am Soc Nephrol. 2010;21:93–102.
99. Barnes JL, Gorin Y. Myofibroblast differentiation during fibrosis: role of NAD(P)H oxidases. Kidney Int. 2011;79:944–56.
100. Alili L, Sack M, Puschmann K, Brenneisen P. Fibroblast-to-myofibroblast switch is mediated by NAD(P)H oxidase generated reactive oxygen species. Biosci Rep. 2013.
101. Siani A, Tirelli N. Myofibroblast differentiation: main features, biomedical relevance, and the role of reactive oxygen species. Antioxid Redox Signal. 2014;21:768–85.
102. Shen WL, Gao PJ, Che ZQ, Ji KD, Yin M, Yan C, et al. NAD(P)H oxidase-derived reactive oxygen species regulate angiotensin-II induced adventitial fibroblast phenotype differentiation. Biochem Biophys Res Commun. 2006;339:337–43.
103. Amara N, Goven D, Prost F, Muloway R, Crestani B, Boczkowski J. NOX4/NADPH oxidase expression is increased in pulmonary fibroblasts from patients with idiopathic pulmonary fibrosis and mediates TGFbeta-1-induced fibroblast differentiation into myofibroblasts. Thorax. 2010;65:733–8.
104. Paik YH, Kim J, Aoyama T, De Minicis S, Bataller R, Brenner DA. Role of NADPH oxidase in liver fibrosis. Antioxid Redox Signal. 2014;20:2854–72.
105. Babalola O, Mamalis A, Lev-Tov H, Jagdeo J. NADPH oxidase enzymes in skin fibrosis: molecular targets and therapeutic agents. Arch Dermatol Res. 2014;306:313–30.
106. Böhm M, Dosoki H, Kerkhoff C. Is Nox4 a key regulator of the activated state of fibroblasts in systemic sclerosis? Exp Dermatol. 2014. doi:10.1111/exd.12497.
107. Montorfano I, Becerra A, Cerro R, Echeverria C, Saez E, Morales MG, et al. Oxidative stress mediates the conversion of endothelial cells into myofibroblasts via a TGF-β1 and TGF-β2-dependent pathway. Lab Invest. 2014. doi:10.1038/labinvest.2014.100. Important study showing that oxidative stress was capable of inducing a phenotypic change of endothelial cells into myofibroblasts through a TGF-β dependent mechanism.
108. Serrander L, Cartier L, Bedard K, Bandi B, Lardy B, Plastre O. NOX4 activity is determined by mRNA levels and reveals a unique pattern of ROS generation. Biochem J. 2007;406:105–14.
109. Jiang F, Liu GS, Dusting GJ, Chan EC. NADPH oxidase-dependent redox signaling in TGF-β-mediated fibrotic responses. Redox Biol. 2014;2:267–72.
110. Bai G, Hock TD, Logsdon N, Zhou Y, Thannickal VJ. A far-upstream AP-1/Smad binding box regulates human NOX4 promoter activation by transforming growth factor-β. Gene. 2014;540:62–7.
111. Lyle AN, Deshpande NN, Taniyama Y, Seidel-Rogol B, Pounkova L, Du P, et al. Poldip2, a novel regulator of Nox4 and cytoskeletal integrity in vascular smooth muscle cells. Circ Res. 2009;105:249–59. This paper describes the exciting new findings that polymerase delta interacting protein 2 (Poldip2) interacts with NOX4 and is capable of increasing NOX4 activity by three-fold.
112. Simonini G, Pignone A, Generini S, Falcini F, Cerinic MM. Emerging potentials for an antioxidant therapy as a new approach to the treatment of systemic sclerosis. Toxicology. 2000;155:1–15.
113. Erre GL, De Muro P, Dellaca P, et al. Iloprost therapy acutely decreases oxidative stress in patients affected by systemic sclerosis. Clin Exp Rheumatol. 2008;26:1095–8.
114. Volpe A, Biasi D, Caramaschi P, et al. Iloprost infusion does not reduce oxidative stress in systemic sclerosis. Rheumatol Int. 2008;28:335–7.
115. Erre GL, Passiu G. Antioxidant effect of iloprost: current knowledge and therapeutic implications for systemic sclerosis. Reumatismo. 2009;61:90–7.
116. Yoshizaki A, Yanaba K, Ogawa A, et al. The specific free radical scavenger edaravone suppresses fibrosis in the bleomycin-induced and tight skin mouse models of systemic sclerosis. Arthritis Rheum. 2011;63:3086–97.
117. Marut WK, Kavian N, Servettaz A, et al. The organotelluride catalyst (PHTE)NQ prevents HOCl-induced systemic sclerosis in mouse. J Invest Dermatol. 2012;132:1125–32.
118. Sambo P, Amico D, Giacomelli R, et al. Intravenous N-acetylcysteine for treatment of Raynaud’s phenomenon secondary to systemic sclerosis: a pilot study. J Rheumatol. 2001;28:2257–62.
119. Cracowski JL, Girolet S, Imbert B, et al. Effects of short-term treatment with vitamin E in systemic sclerosis: a double blind, randomized, controlled clinical trial of efficacy based on urinary isoprostane measurement. Free Radic Biol Med. 2005;38:98–103.
120. Rosato E, Rossi C, Molinaro I, Giovannetti A, Pisarri S, Salsano F. Long-term N-acetylcysteine therapy in systemic sclerosis interstitial lung disease: a retrospective study. Int J Immunopathol Pharmacol. 2011;24:727–33.
121. Allanore Y, Borderie D, Perianin A, Lemarechal H, Ekindjian OG, Kahan A. Nifedipine protects against overproduction of superoxide anion by monocytes from patients with systemic sclerosis. Arthritis Res Ther. 2005;7:R93–R100.
122. Furst DE, Clements PJ, Harris R, Ross M, Levy J, Paulus HE. Measurement of clinical change in progressive systemic sclerosis: a 1 year double-blind placebo-controlled trial of N-acetylcysteine. Ann Rheum Dis. 1979;38:356–61.
123. Laleu B, Gaggini F, Orchard M, Fioraso-Cartier L, Cagnon L, Houngninou-Molango S, et al. First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic fibrosis. J Med Chem. 2010;53:7715–30.
124. Gaggini F, Laleu B, Orchard M, Fioraso-Cartier L, Cagnon L, Houngninou-Molango S, et al. Design, synthesis and biological activity of original pyrazolo-pyrido-diazepine,-pyrazine and -oxazine dione derivatives as a novel dual Nox4/Nox1 inhibitors. Bioorg Med Chem. 2011;19:6989–99. References 123 and 124 describe the design and synthesis of a novel class of potent and highly selective NOX4 small molecule inhibitors.
125. El-Benna J, Dang PM, Perianin A. Towards specific NADPH oxidase inhibition by small synthetic peptides. Cell Mol Life Sci. 2012;69:2307–14. Description of novel and specific small synthetic peptides targeting NOX enzymes.
126. Altenhöfer S, Radermacher KA, Kleikers PW, Wingler K, Schmidt HH. Evolution of NADPH oxidase inhibitors: selectivity and mechanisms for target engagement. Antioxid Redox Signal. 2014.
127. Altenhöfer S, Kleikers PW, Radermacher KA, Scheurer P, Rob Hermans JJ, Schiffers P, et al. The NOX toolbox: validating the role of NADPH oxidases in physiology and disease. Cell Mol Life Sci. 2012;69:2327–43.
128. Kim JA, Neupane GP, Lee ES, Jeong BS, Park BC, Thapa. NADPH oxidase inhibitors: a patent review. Expert Opin Ther Patent. 2011;21:1147–58.
129. Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F, Fioraso-Cartier L, et al. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology. 2012;56:2316–27.
130. Jarman ER, Khambata VS, Cope C, Jones P, Roger J, Ye LY, et al. An inhibitor of NADPH oxidase-4 attenuates established pulmonary fibrosis in a rodent disease model. Am J Respir Cell Mol Biol. 2014;50:158–69. Highly relevant study demonstrating that inhibition of NOX4 activity employing a small molecule antagonist decreased TGF-β1-induced upregulation of profibrotic genes in normal human lung fibroblasts in vitro and attenuated established lung fibrosis in vivo in bleomycin-induced animal model of pulmonary fibrosis.
131. Hecker L, Logsdon NJ, Kurundkar D, Kurundkar A, Bernard K, Hock T, et al. Reversal of persistent fibrosis in aging by targeting Nox4-Nrf2 redox imbalance. Sci Transl Med. 2014;6:231ra47. doi:10.1126/scitranslmed.3008182. This interesting study demonstrates that aged mice display persistent lung fibrosis following intratracheal bleomycin administration whereas young mice resolve the fibrotic process. The mechanisms involve NOX4/Nrf2 redox imbalance-induced fibroblast senescence coupled with apoptosis resistance causing a failure to resolve fibrosis.
132. Sampson N, Berger P, Zenzmaier C. Redox signaling as a therapeutic target to inhibit myofibroblast activation in degenerative fibrotic disease. Biomed Res Int. 2014;2014:131737. doi:10.1155/2014/131737.