title: Increased DNA damage in progression of COPD: a response by poly(ADP-ribose) polymerase-1.
abstract: Chronic oxidative stress (OS), a major mechanism of chronic obstructive pulmonary disease (COPD), may cause significant damage to DNA. Poly(ADP-ribose) polymerase (PARP)-1 is rapidly activated by OS-induced DNA lesions. However, the degree of DNA damage along with the evolution of COPD is unclear. In peripheral blood mononuclear cells of non-smoking individuals, non-obstructive smokers, patients with COPD of all stages and those with COPD exacerbation, we evaluated DNA damage, PARP activity and PARP-1 mRNA expression using Comet Assay IV, biotinylated-NAD incorporation assay and qRT-PCR, respectively and subjected results to ordinal logistic regression modelling. Adjusted for demographics, smoking-related parameters and lung function, novel comet parameters, tail length/cell length ratio and tail migration/cell length ratio, showed the greatest increase along the study groups corresponding to the evolution of COPD [odds ratio (OR) 7.88, 95% CI 4.26-14.57; p<0.001 and OR 3.91, 95% CI 2.69-5.66; p<0.001, respectively]. Analogously, PARP activity increased significantly over the groups (OR = 1.01; 95%; p<0.001). An antioxidant tetrapeptide UPF17 significantly reduced the PARP-1 mRNA expression in COPD, compared to that in non-obstructive individuals (p = 0.040). Tail length/cell length and tail migration/cell length ratios provide novel progression-sensitive tools for assessment of DNA damage. However, it remains to be elucidated whether inhibition of an elevated PARP-1 activity has a safe enough potential to break the vicious cycle of the development and progression of COPD.
authors.affiliation: Department of Pulmonary Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia. Ingrid.Oit-Wiscombe@ut.ee
authors.forename: Ingrid
authors.initials: I
authors.lastname: Oit-Wiscombe
authors.forename: Laszlo
authors.initials: L
authors.lastname: Virag
authors.forename: Ursel
authors.initials: U
authors.lastname: Soomets
authors.forename: Alan
authors.initials: A
authors.lastname: Altraja
mesh_terms: D000368:Aged; D020552:Comet Assay; D004249:DNA Damage / Q000235:genetics*; D005260:Female; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics*
chemical_list: C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
references.citation: J Histochem Cytochem. 2002 Jan;50(1):91-8
references.pmid: 11748298
references.citation: Int J Chron Obstruct Pulmon Dis. 2012;7:641-52
references.pmid: 23055713
references.citation: J Chromatogr B Biomed Sci Appl. 1999 Feb 5;722(1-2):225-54
references.pmid: 10068143
references.citation: Respir Med. 2006 Jul;100(7):1270-6
references.pmid: 16307872
references.citation: Mutat Res. 2000 Jun 30;460(1):1-15
references.pmid: 10856830
references.citation: Mol Aspects Med. 2013 Dec;34(6):1217-56
references.pmid: 23370117
references.citation: Genes Dev. 2005 Sep 1;19(17):1951-67
references.pmid: 16140981
references.citation: Pharmacol Rev. 2002 Sep;54(3):375-429
references.pmid: 12223530
references.citation: J Pharmacol Exp Ther. 2005 Nov;315(2):812-20
references.pmid: 16079296
references.citation: Allergy. 2011 Jul;66(7):853-61
references.pmid: 21276008
references.citation: Free Radic Biol Med. 2009 Jul 1;47(1):13-26
references.pmid: 19362586
references.citation: Biochem J. 1999 Sep 1;342 ( Pt 2):249-68
references.pmid: 10455009
references.citation: Am J Physiol Gastrointest Liver Physiol. 2000 Sep;279(3):G641-51
references.pmid: 10960365
references.citation: Mutat Res. 2007 Jan 10;626(1-2):180-4
references.pmid: 17070727
references.citation: Am J Pathol. 2011 Mar;178(3):946-55
references.pmid: 21356345
references.citation: Neurochem Int. 2013 Apr;62(5):664-73
references.pmid: 23357477
references.citation: J Environ Public Health. 2012;2012:472751
references.pmid: 22523504
references.citation: Biochem J. 2011 Jun 15;436(3):671-9
references.pmid: 21434873
references.citation: Annu Rev Physiol. 2009;71:451-64
references.pmid: 18817512
references.citation: Am J Respir Cell Mol Biol. 2003 Mar;28(3):322-9
references.pmid: 12594058
references.citation: Trends Pharmacol Sci. 1998 Jul;19(7):287-98
references.pmid: 9703762
references.citation: Pharmacol Res. 2005 Jul;52(1):83-92
references.pmid: 15911336
references.citation: Proc Am Thorac Soc. 2005;2(4):367-70; discussion 371-2
references.pmid: 16267364
references.citation: Shock. 2006 Jun;25(6):633-40
references.pmid: 16721272
references.citation: FEBS Lett. 2012 Nov 2;586(21):3771-7
references.pmid: 23022557
references.citation: Nat Rev Drug Discov. 2005 May;4(5):421-40
references.pmid: 15864271
references.citation: Free Radic Biol Med. 2003 Jul 15;35(2):140-8
references.pmid: 12853070
references.citation: Free Radic Res. 2007 Jul;41(7):779-87
references.pmid: 17577738
references.citation: Arch Biochem Biophys. 2010 Aug 15;500(2):203-9
references.pmid: 20493163
references.citation: FASEB J. 1987 Nov;1(5):358-64
references.pmid: 2824268
references.citation: Aging (Albany NY). 2009 May 20;1(5):458-69
references.pmid: 20157531
references.citation: Int J Pept. 2012;2012:124163
references.pmid: 22611414
references.citation: Free Radic Biol Med. 2012 Nov 1;53(9):1680-8
references.pmid: 22964577
references.citation: Med Sci Monit. 2004 Mar;10(3):BR77-83
references.pmid: 14976461
references.citation: Eur Respir J Suppl. 2003 Nov;46:14s-27s
references.pmid: 14621103