title: Sustained expression of NADPH oxidase 4 by p38 MAPK-Akt signaling potentiates radiation-induced differentiation of lung fibroblasts.
abstract: Radiation-induced fibrosis (RIF) is a long-term adverse effect of curative radiotherapy; however, the distinct molecular mechanisms of RIF in neighboring normal tissue are not fully understood. We investigated the mechanisms underlying radiation-induced fibroblast differentiation into myofibroblasts. Lung fibroblasts produced reactive oxygen species (ROS) immediately after irradiation, the level of which remained increased for 24 h. The NADPH oxidase inhibitor, diphenyleneiodonium (DPI), suppressed ROS production and significantly decreased the radiation-induced expression of alpha-smooth muscle actin (alpha-SMA) and fibronectin (FN). The mRNA and protein expression of Nox4 was increased by radiation, and siRNA knockdown of Nox4 reduced alpha-SMA and FN levels. Increased phosphorylation of p38MAPK, Erk, and PI3k/Akt was observed after irradiation. Inhibitors of p38 MAPK and Akt, but not of Erk, reduced radiation-induced fibroblast differentiation and Nox4 expression. Notably, DPI partially decreased phosphorylation of p38MAPK and Akt, suggesting that p38MAPK, Akt, and Nox4 may cooperate in a positive feedback loop. Nox4 expression was also increased during bleomycin-induced fibroblast differentiation, and downregulation of Nox4 reduced alpha-SMA levels and extracellular matrix (ECM) accumulation. These results demonstrate that interfering Nox4 activation can be a potential strategy to disrupt fibrotic process.
authors.affiliation: Laboratory of Radiation Sensitization & Protection, Korea Institute of Radiological & Medical Sciences, 215-4, Gongneung-dong, Nowon-gu, Seoul, 139-706, Republic of Korea.
authors.forename: Sarah
authors.initials: S
authors.lastname: Park
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Ahn
authors.forename: Min-Jin
authors.initials: MJ
authors.lastname: Lim
authors.forename: Mi-Hyoung
authors.initials: MH
authors.lastname: Kim
authors.forename: Yeon-Sook
authors.initials: YS
authors.lastname: Yun
authors.forename: Gajin
authors.initials: G
authors.lastname: Jeong
authors.forename: Jie-Young
authors.initials: JY
authors.lastname: Song
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D002454:Cell Differentiation / Q000528:radiation effects*; D002460:Cell Line; D005347:Fibroblasts / Q000166:cytology / Q000528:radiation effects*; D005786:Gene Expression Regulation / Q000528:radiation effects; D006801:Humans; D008168:Lung / Q000166:cytology*; D032446:Myoblasts / Q000166:cytology; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000903:Antibiotics, Antineoplastic; D017382:Reactive Oxygen Species; D001761:Bleomycin; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498910:NOX4 protein, human; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases
references.citation: Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G99-G108
references.pmid: 17962358
references.citation: Free Radic Biol Med. 2008 Sep 15;45(6):929-38
references.pmid: 18640264
references.citation: Biochem J. 1987 Feb 15;242(1):103-7
references.pmid: 3036079
references.citation: BMC Cancer. 2006 Mar 24;6:79
references.pmid: 16556328
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Mar;296(3):L489-99
references.pmid: 19036873
references.citation: J Mol Med (Berl). 2009 Jan;87(1):75-84
references.pmid: 18825355
references.citation: Semin Radiat Oncol. 2004 Oct;14(4):298-307
references.pmid: 15558504
references.citation: J Immunol Methods. 2002 Jul 1;265(1-2):49-72
references.pmid: 12072178
references.citation: J Biomed Sci. 2007 May;14(3):303-12
references.pmid: 17334833
references.citation: Nat Med. 2009 Sep;15(9):1077-81
references.pmid: 19701206
references.citation: Biochim Biophys Acta. 2005 Mar 11;1722(2):143-7
references.pmid: 15716123
references.citation: Int J Oncol. 2001 Nov;19(5):1057-61
references.pmid: 11605009
references.citation: Toxicol Appl Pharmacol. 2009 May 15;237(1):111-8
references.pmid: 19268487
references.citation: J Radiat Res. 1999 Dec;40(4):323-35
references.pmid: 10748578
references.citation: Hypertension. 2001 Feb;37(2 Pt 2):535-40
references.pmid: 11230331
references.citation: Circ Res. 2005 Oct 28;97(9):900-7
references.pmid: 16179589
references.citation: Toxicol Appl Pharmacol. 2006 May 1;212(3):179-87
references.pmid: 16120450
references.citation: Arterioscler Thromb Vasc Biol. 2008 May;28(5):878-85
references.pmid: 18309110
references.citation: Chest. 2007 Oct;132(4):1311-21
references.pmid: 17934117
references.citation: Dtsch Med Wochenschr. 2009 Mar;134(11):524-9
references.pmid: 19259911
references.citation: Am J Respir Crit Care Med. 2006 Dec 15;174(12):1352-60
references.pmid: 17023731
references.citation: Cancer Res. 1997 Sep 15;57(18):3963-71
references.pmid: 9307280
references.citation: Cancer Res. 2001 May 15;61(10):3894-901
references.pmid: 11358802
references.citation: Biochem Biophys Res Commun. 2006 Jan 6;339(1):337-43
references.pmid: 16298339
references.citation: J Am Soc Nephrol. 2005 Mar;16(3):667-75
references.pmid: 15677311
references.citation: Int J Radiat Oncol Biol Phys. 2003 Jun 1;56(2):561-72
references.pmid: 12738334
references.citation: Am J Physiol Lung Cell Mol Physiol. 2009 Nov;297(5):L805-12
references.pmid: 19648289
references.citation: Pulm Pharmacol Ther. 2009 Dec;22(6):487-91
references.pmid: 19393328
references.citation: Int J Radiat Oncol Biol Phys. 2003 Oct 1;57(2):563-72
references.pmid: 12957270
references.citation: J Exp Med. 2005 Mar 21;201(6):925-35
references.pmid: 15781583
references.citation: Free Radic Biol Med. 2008 Mar 15;44(6):938-55
references.pmid: 18164271
references.citation: Thorax. 1993 Oct;48(10):959-66
references.pmid: 7504843
references.citation: Ther Adv Respir Dis. 2008 Oct;2(5):319-38
references.pmid: 19124380
references.citation: Mol Biol Cell. 2006 Sep;17(9):3978-88
references.pmid: 16775014
references.citation: Biochem Biophys Res Commun. 2002 May 24;293(5):1571-8
references.pmid: 12054696