Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Antioxidants / metabolism
-
Bronchi / cytology
-
Bronchoalveolar Lavage
-
Cell Line
-
Cell Proliferation / drug effects
-
Cystic Fibrosis / complications*
-
Cystic Fibrosis / prevention & control*
-
Cystic Fibrosis Transmembrane Conductance Regulator / antagonists & inhibitors
-
Cystic Fibrosis Transmembrane Conductance Regulator / metabolism
-
Disease Models, Animal
-
Epithelial Cells / drug effects
-
Epithelial Cells / metabolism
-
Epithelial Cells / pathology
-
Flagellin / administration & dosage
-
Flagellin / pharmacology
-
Humans
-
Inflammation / complications*
-
Inflammation / prevention & control*
-
Inflammation Mediators / metabolism
-
Interleukin-8 / metabolism
-
Lipopolysaccharides / pharmacology
-
Mice
-
NF-E2-Related Factor 2 / metabolism
-
NF-kappa B / metabolism
-
Neutrophils / cytology
-
Neutrophils / drug effects
-
Oleanolic Acid / administration & dosage
-
Oleanolic Acid / analogs & derivatives*
-
Oleanolic Acid / pharmacology
-
Oxidation-Reduction / drug effects
-
Proteomics
-
Trachea / cytology
-
Triterpenes / administration & dosage
-
Triterpenes / pharmacology*
Substances
-
2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid
-
Antioxidants
-
Inflammation Mediators
-
Interleukin-8
-
Lipopolysaccharides
-
NF-E2-Related Factor 2
-
NF-kappa B
-
Triterpenes
-
Cystic Fibrosis Transmembrane Conductance Regulator
-
Flagellin
-
Oleanolic Acid