title: Cigarette smoke-induced collagen destruction; key to chronic neutrophilic airway inflammation?
abstract: BACKGROUND
  Cigarette smoking induces inflammatory responses in all smokers and is the major risk factor for lung disease such as chronic obstructive pulmonary disease (COPD). In this progressive disease, chronic inflammation in the lung contributes to lung tissue destruction leading to the formation of chemotactic collagen fragments such as N-acetylated Proline-Glycine-Proline (N-ac-PGP). The generation of this tripeptide is mediated by a multistep pathway involving matrix metalloproteases (MMPs) 8 and 9 and prolyl endopeptidase (PE). Here we investigated whether cigarette smoke extract (CSE) stimulates human PMNs to breakdown whole matrix collagen leading to the generation of the chemotactic collagen fragment N-ac-PGP.
  
  
  RESULTS
  Incubating PMNs with CSE led to the release of chemo-attractant CXCL8 and proteases MMP8 and MMP9. PMNs constitutively expressed PE activity as well as PE protein. Incubating CSE-primed PMNs with collagen resulted in collagen breakdown and in N-ac-PGP generation. Incubation of PMNs with the tripeptide N-ac-PGP resulted in the release of CXCL8, MMP8 and MMP9. Moreover, we tested whether PMNs from COPD patients are different from PMNs from healthy donors. Here we show that the intracellular basal PE activity of PMNs from COPD patients increased 25-fold compared to PMNs from healthy donors. Immunohistological staining of human lung tissue for PE showed that besides neutrophils, macrophages and epithelial cells express PE.
  
  
  CONCLUSIONS
  This study indicates that neutrophils activated by cigarette smoke extract can breakdown collagen into N-ac-PGP and that this collagen fragment itself can activate neutrophils, which may lead in vivo to a self-propagating cycle of neutrophil infiltration, chronic inflammation and lung emphysema. MMP-, PE- or PGP-inhibitors can serve as an attractive therapeutic target and may open new avenues towards effective treatment of COPD.
authors: Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, The Netherlands.
authors: Saskia A
authors: SA
authors: Overbeek
authors: Saskia
authors: S
authors: Braber
authors: Pim J
authors: PJ
authors: Koelink
authors: Paul A J
authors: PA
authors: Henricks
authors: Esmaeil
authors: E
authors: Mortaz
authors: Adele T
authors: AT
authors: LoTam Loi
authors: Patricia L
authors: PL
authors: Jackson
authors: Johan
authors: J
authors: Garssen
authors: Gerry T M
authors: GT
authors: Wagenaar
authors: Wim
authors: W
authors: Timens
authors: Leo
authors: L
authors: Koenderman
authors: J Edwin
authors: JE
authors: Blalock
authors: Aletta D
authors: AD
authors: Kraneveld
authors: Gert
authors: G
authors: Folkerts
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D002470:Cell Survival / Q000187:drug effects; D003094:Collagen / Q000276:immunology* / Q000378:metabolism; D024042:Collagen Type I / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology* / Q000473:pathology*; D016209:Interleukin-8 / Q000096:biosynthesis; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D008875:Middle Aged; D009504:Neutrophils / Q000276:immunology*; D009842:Oligopeptides / Q000096:biosynthesis / Q000494:pharmacology; D011392:Proline / Q000031:analogs & derivatives / Q000096:biosynthesis / Q000494:pharmacology; D000085822:Prolyl Oligopeptidases; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology / Q000473:pathology; D012697:Serine Endopeptidases / Q000378:metabolism; D012907:Smoking / Q000009:adverse effects*; D062789:Tobacco Products / Q000009:adverse effects
chemical_list: D024042:Collagen Type I; D016209:Interleukin-8; D009842:Oligopeptides; C113164:prolyl-glycyl-proline; D003094:Collagen; D011392:Proline; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9
references: Lancet. 2007 Sep 1;370(9589):765-73
references: 17765526
references: Nat Med. 2006 Mar;12(3):280-1
references: 16520772
references: Respir Res. 2005 Dec 22;6:151
references: 16372907
references: Eur J Pharmacol. 2011 Oct 15;668(3):428-34
references: 21458443
references: Chest. 2003 Apr;123(4):1240-7
references: 12684317
references: Am J Physiol Lung Cell Mol Physiol. 2011 Feb;300(2):L255-65
references: 21112944
references: J Immunol. 2008 Apr 15;180(8):5662-9
references: 18390751
references: J Allergy Clin Immunol. 2007 May;119(5):1065-71
references: 17270263
references: Science. 2010 Oct 1;330(6000):90-4
references: 20813919
references: Respir Res. 2009 May 18;10:38
references: 19450278
references: J Neuroimmunol. 2009 Dec 10;217(1-2):51-4
references: 19875179
references: Front Biosci. 2008 Jan 01;13:2400-7
references: 17981721
references: Eur Respir J. 2003 Oct;22(4):672-88
references: 14582923
references: Respir Res. 2011 Jun 08;12:75
references: 21651795
references: J Immunol. 2009 Apr 1;182(7):4423-31
references: 19299743
references: Med Princ Pract. 2010;19(5):330-8
references: 20639653
references: Crit Rev Toxicol. 1991;21(4):235-40
references: 2069709
references: Eur J Pharmacol. 2011 Oct 15;668(3):443-9
references: 21458445
references: Chest. 2004 Dec;126(6):1802-10
references: 15596677
references: J Exp Med. 1991 Mar 1;173(3):771-4
references: 1997655
references: Chest. 2011 Jun;139(6):1380-1387
references: 20966041
references: Am J Physiol Lung Cell Mol Physiol. 2003 Apr;284(4):L566-77
references: 12618418
references: Int J Chron Obstruct Pulmon Dis. 2007;2(3):369-79
references: 18229576
references: BMC Pulm Med. 2009 May 27;9:25
references: 19473482
references: Proc Am Thorac Soc. 2009 Sep 15;6(6):524-6
references: 19741261
references: Invest Ophthalmol Vis Sci. 1998 Aug;39(9):1744-50
references: 9699566
references: J Appl Physiol (1985). 2005 May;98(5):1892-9
references: 15829722
references: PLoS One. 2011 Jan 13;6(1):e15781
references: 21249198
references: J Physiol Pharmacol. 2008 Dec;59 Suppl 6:19-34
references: 19218630
references: Scand J Clin Lab Invest. 2008;68(7):618-23
references: 19378434
references: Pharmacol Rev. 2004 Dec;56(4):515-48
references: 15602009
references: Nat Med. 2006 Mar;12(3):317-23
references: 16474398
references: Respir Res. 2006 Apr 19;7:66
references: 16620395