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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-l,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-[kappa]B 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. anti-inflammatory therapy; antioxidant; nuclear factor-[kappa]B; nuclear factor erythroid-related factor 2; synthetic triterpenoid doi: 10.1152/ajplung.00171.2009.

The pathophysiology of cystic fibrosis (CF) inflammatory lung disease is not well understood. CF airway epithelial cells respond to inflammatory stimuli with increased production of proinflammatory cytokines as a result of increased NF-[kappa]B activation. Peroxisome proliferator-activated receptor-[gamma] (PPA[R[gamma]) inhibits NF-[kappa]B activity and is reported to be reduced in CF. If PPAR[gamma] participates in regulatory dysfunction in the CF lung, perhaps PPAR[gamma] ligands might be useful therapeutically. Cell models of CF airway epithelium were used to evaluate PPAR[gamma] expression and binding to NF-[kappa]B at basal and under conditions of inflammatory stimulation by Pseudomonas aeruginosa or TNF[alpha]/IL-1[beta]. An animal model of CF was used to evaluate the potential of PPAR[gamma] agonists as therapeutic agents in vivo. In vitro, PPAR[gamma] agonists reduced IL-8 and MMP-9 release from airway epithelial cells in response to PAO1 or TNF[alpha]/IL-1[beta] stimulation. Less NF-[kappa]B bound to PPAR[gamma] in CF than normal cells, in two different assays; PPAR[gamma] agonists abrogated this reduction. PPAR[gamma] bound less to its target DNA sequence in CF cells. To test the importance of the reported PPAR[gamma] inactivation by phosphorylation, we observed that inhibitors of ERK, but not JNK, were synergistic with PPAR[gamma] agonists in reducing IL-8 secretion. In vivo, administration of PPAR[gamma] agonists reduced airway inflammation in response to acute infection with P. aeruginosa in CF, but not wildtype, mice. In summary, PPAR[gamma] inhibits the inflammatory response in CF, at least in part by interaction with NF-[kappa]B in airway epithelial cells. PPAR[gamma] agonists may be therapeutic in CF. nuclear factor-[kappa]B; cytokines; disease models; animal; in vitro; lung diseases; Pseudomonas aeruginosa