The triterpenoid CDDO limits inflammation in preclinical models of cystic fibrosis lung disease.
Excessive inflammation in cystic fibrosis (CF) lung disease is a contributor to progressive pulmonary decline. Effective and well-tolerated anti-inflammatory therapy may preserve lung function, thereby improving quality and length of life. In this paper, we assess the anti-inflammatory effects of the synthetic triterpenoid 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO) in preclinical models of CF airway inflammation. In our experiments, mice carrying the R117H Cftr mutation have significantly reduced airway inflammatory responses to both LPS and flagellin when treated with CDDO before inflammatory challenge. Anti-inflammatory effects observed include reduced airway neutrophilia, reduced concentrations of proinflammatory cytokines and chemokines, and reduced weight loss. Our findings with the synthetic triterpenoids in multiple cell culture models of CF human airway epithelia agree with effects previously described in other disease models (e.g., neoplastic cells). These include the ability to reduce NF-kappaB activation while increasing nuclear factor erythroid-related factor 2 (Nrf2) activity. As these two signaling pathways appear to be pivotal in regulating the net inflammatory response in the CF airway, these compounds are a promising potential anti-inflammatory therapy for CF lung disease.
Nichols
David P
DP
Department of Pediatrics, National Jewish Health K1026, 1400 Jackson St., Denver, CO 80206, USA. nicholsd@njhealth.org
Ziady
Assem G
AG
Shank
Samuel L
SL
Eastman
Jean F
JF
Davis
Pamela B
PB
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001980:Bronchi / Q000166:cytology; D018893:Bronchoalveolar Lavage; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003550:Cystic Fibrosis / Q000150:complications* / Q000517:prevention & control*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005408:Flagellin / Q000008:administration & dosage / Q000494:pharmacology; D006801:Humans; D007249:Inflammation / Q000150:complications* / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D010084:Oxidation-Reduction / Q000187:drug effects; D040901:Proteomics; D014132:Trachea / Q000166:cytology; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology*
C116817:2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; D000975:Antioxidants; D018836:Inflammation Mediators; D016209:Interleukin-8; D008070:Lipopolysaccharides; D051267:NF-E2-Related Factor 2; D016328:NF-kappa B; D014315:Triterpenes; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D005408:Flagellin; D009828:Oleanolic Acid
Am J Respir Crit Care Med. 1994 Aug;150(2):448-54
8049828
Am J Respir Cell Mol Biol. 1993 May;8(5):522-9
7683197
J Infect Dis. 1997 Mar;175(3):638-47
9041336
J Allergy Clin Immunol. 1999 Jul;104(1):72-8
10400842
J Biol Chem. 2006 Apr 21;281(16):11279-91
16455659
Am J Respir Crit Care Med. 2007 Dec 1;176(11):1084-9
17872492
Invest Ophthalmol Vis Sci. 2009 Nov;50(11):5339-47
19494206
Clin Cancer Res. 2006 Jul 15;12(14 Pt 1):4288-93
16857804
Am J Respir Crit Care Med. 1997 Oct;156(4 Pt 1):1197-204
9351622
PLoS One. 2008;3(10):e3367
18846238
J Pediatr. 2007 Sep;151(3):249-54
17719932
J Clin Invest. 2005 Sep;115(9):2564-71
16127463
Am J Physiol Lung Cell Mol Physiol. 2007 Feb;292(2):L383-95
16920886
Pediatr Pulmonol. 1995 Aug;20(2):63-70
8570304
Chest. 1999 Apr;115(4):1053-8
10208207
Am J Respir Crit Care Med. 1996 Nov;154(5):1229-56
8912731
Mol Cancer Ther. 2006 Dec;5(12):3232-9
17148759
Respirology. 2007 Jan;12(1):63-9
17207027
Am J Respir Cell Mol Biol. 2000 Sep;23(3):396-403
10970832
Am J Respir Crit Care Med. 1995 Apr;151(4):1075-82
7697234
Am J Physiol Lung Cell Mol Physiol. 2001 Jul;281(1):L71-8
11404248
J Biol Chem. 2006 Nov 24;281(47):35764-9
16998237
Am J Physiol Lung Cell Mol Physiol. 2004 Nov;287(5):L944-52
15246977
Am J Respir Crit Care Med. 1999 Jul;160(1):186-91
10390398
Proc Natl Acad Sci U S A. 2005 Mar 22;102(12):4584-9
15767573
Clin Rev Allergy Immunol. 2002 Aug;23(1):5-27
12162106
Am J Physiol Lung Cell Mol Physiol. 2003 Feb;284(2):L307-15
12388360
N Engl J Med. 1995 Mar 30;332(13):848-54
7503838
Mol Cancer Ther. 2007 Jan;6(1):154-62
17237276
Proc Natl Acad Sci U S A. 1980 Sep;77(9):5216-20
6933553
Am J Physiol Lung Cell Mol Physiol. 2001 Jul;281(1):L31-8
11404242
BMJ. 1995 Jun 17;310(6994):1571-2
7787647
J Clin Invest. 1998 Jun 1;101(11):2598-605
9616231
J Immunol. 2008 Apr 15;180(8):5662-9
18390751
Clin Cancer Res. 2006 Mar 15;12(6):1828-38
16551868
Pediatr Pulmonol. 1997 Aug;24(2):137-42; discussion 159-61
9292910
Treat Respir Med. 2005;4(4):255-73
16086599
Am J Respir Cell Mol Biol. 2006 Nov;35(5):579-86
16763223
J Biol Chem. 2006 Jan 20;281(3):1495-505
16286467
J Immunol. 2004 Feb 15;172(4):2522-9
14764725
Methods Mol Biol. 2002;188:115-37
11987537
Am J Respir Crit Care Med. 1994 Jul;150(1):207-13
7912987
Biochem Pharmacol. 2007 Jun 15;73(12):1982-94
17466952
Am Rev Respir Dis. 1993 Oct;148(4 Pt 1):896-901
8214945
Am J Respir Cell Mol Biol. 2000 Sep;23(3):304-12
10970820