Increased cytokine response of rhinovirus-infected airway epithelial cells in chronic obstructive pulmonary disease.
BACKGROUND
Airway inflammation is a central feature of chronic obstructive pulmonary disease (COPD). COPD exacerbations are often triggered by rhinovirus (RV) infection.


OBJECTIVE
We hypothesized that airway epithelial cells from patients with COPD maintain a proinflammatory phenotype compared with control subjects, leading to greater RV responses.


METHODS
Cells were isolated from tracheobronchial tissues of 12 patients with COPD and 10 transplant donors. Eight patients with COPD had severe emphysema, three had mild to moderate emphysema, and one had no emphysema. All had moderate to severe airflow obstruction, and six met criteria for chronic bronchitis or had at least one exacerbation the previous year. Cells were grown at air-liquid interface and infected with RV serotype 39. Cytokine and IFN expression was measured by ELISA. Selected genes involved in inflammation, oxidative stress, and proteolysis were assessed by focused gene array and real-time polymerase chain reaction.


RESULTS
Compared with control subjects, cells from patients with COPD demonstrated increased mRNA expression of genes involved in oxidative stress and the response to viral infection, including NOX1, DUOXA2, MMP12, ICAM1, DDX58/RIG-I, STAT1, and STAT2. COPD cells showed elevated baseline and RV-stimulated protein levels of IL-6, IL-8/CXCL8, and growth-related oncogene-alpha/CXCL1. COPD cells demonstrated increased viral titer and copy number after RV infection, despite increased IL-29/IFN-lambda1, IL-28A/IFN-lambda2, and IFN-inducible protein-10/CXCL10 protein levels. Finally, RV-infected COPD cultures showed increased mRNA expression of IL28A/IFNlambda2, IL29/IFNlambda1, IFIH1/MDA5, DDX58/RIG-I, DUOX1, DUOX2, IRF7, STAT1, and STAT2.


CONCLUSIONS
Airway epithelial cells from patients with COPD show higher baseline levels of cytokine expression and increased susceptibility to RV infection, despite an increased IFN response.
Schneider
Dina
D
University of Michigan, Ann Arbor, MI 48109-5688, USA.
Ganesan
Shyamala
S
Comstock
Adam T
AT
Meldrum
Catherine A
CA
Mahidhara
Raja
R
Goldsmith
Adam M
AM
Curtis
Jeffrey L
JL
Martinez
Fernando J
FJ
Hershenson
Marc B
MB
Sajjan
Umadevi
U
D000368:Aged; D001980:Bronchi / Q000166:cytology; D016022:Case-Control Studies; D002478:Cells, Cultured; D003139:Common Cold / Q000276:immunology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000473:pathology / Q000821:virology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018384:Oxidative Stress; D029424:Pulmonary Disease, Chronic Obstructive / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D012229:Rhinovirus / Q000276:immunology*; D014132:Trachea / Q000166:cytology; D019562:Viral Load
D016207:Cytokines; D012333:RNA, Messenger
Thorax. 2006 Mar;61(3):196-201
16308335
FASEB J. 2006 Oct;20(12):2121-3
16914605
N Engl J Med. 2005 May 12;352(19):1967-76
15888697
J Clin Invest. 1995 Jul;96(1):549-57
7615827
Am J Respir Crit Care Med. 2004 Jul 15;170(2):141-7
15087294
J Biol Chem. 2005 Nov 4;280(44):36952-61
16120607
Eur Respir J. 2006 Jul;28(1):113-22
16611655
J Infect Dis. 2000 Jun;181(6):1875-84
10837165
Am J Respir Crit Care Med. 2008 May 15;177(10):1111-21
18276942
Thorax. 2003 Jan;58(1):37-42
12511718
Mucosal Immunol. 2010 Jan;3(1):69-80
19710636
J Allergy Clin Immunol. 2004 Apr;113(4):697-702
15100676
Antioxid Redox Signal. 2008 Apr;10(4):705-14
18177232
Nat Med. 2006 Sep;12(9):1023-6
16906156
Am J Respir Crit Care Med. 2001 Nov 1;164(9):1618-23
11719299
J Allergy Clin Immunol. 2009 Jun;123(6):1384-90.e2
19428098
Eur Respir J. 2001 Jun;17(6):1112-9
11491152
Am J Respir Crit Care Med. 2001 Feb;163(2):349-55
11179105
Am J Respir Crit Care Med. 2003 Oct 15;168(8):968-75
12857718
Pulm Pharmacol Ther. 2007;20(5):596-605
16919984
Am J Respir Crit Care Med. 1996 Sep;154(3 Pt 1):813-6
8810624
Free Radic Biol Med. 1996;21(5):669-81
8891669
Thorax. 2002 Jul;57(7):590-5
12096201
Am J Respir Cell Mol Biol. 1999 Jun;20(6):1220-8
10340941
Thorax. 2000 Feb;55(2):114-20
10639527
Proc Natl Acad Sci U S A. 2004 Oct 5;101(40):14461-6
15452344
Infect Immun. 2004 Jul;72(7):4188-99
15213163
J Immunol. 2000 Nov 1;165(9):5211-20
11046054
Am J Respir Crit Care Med. 1997 Mar;155(3):1159-61
9117003
Am J Physiol Lung Cell Mol Physiol. 2007 Oct;293(4):L1021-8
17631613
J Allergy Clin Immunol. 2001 Dec;108(6):997-1004
11742279
Eur Respir J. 2002 Sep;20(3):556-63
12358328
Respir Med. 2007 Dec;101(12):2472-81
17822891
J Exp Med. 2006 Jan 23;203(1):7-13
16380507
J Virol. 2009 Jan;83(1):58-64
18922875
Am J Physiol Lung Cell Mol Physiol. 2001 Jun;280(6):L1115-27
11350790
J Pathol. 2000 Apr;190(5):619-26
10727989
Biochem Biophys Res Commun. 2004 Nov 12;324(2):534-46
15474460
Am J Respir Crit Care Med. 2000 Jul;162(1):167-73
10903237
J Virol. 1999 Apr;73(4):3467-72
10074204
Am J Respir Crit Care Med. 2005 Mar 15;171(6):645-51
15591468
J Infect Dis. 2000 Jun;181(6):1885-90
10837166
Am J Respir Crit Care Med. 2008 Apr 15;177(8):861-70
18174544
J Exp Med. 2005 Mar 21;201(6):937-47
15781584
J Virol. 1993 Jun;67(6):3561-8
8098781
J Allergy Clin Immunol. 2001 Feb;107(2):235-43
11174188