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This Article Full Text Full Text (PDF) All Versions of this Article: 295/2/L303    most recent 90276.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Perez, A. Articles by Davis, P. B. PubMed PubMed Citation Articles by Perez, A. Articles by Davis, P. B.

Peroxisome proliferator-activated receptor- in cystic fibrosis lung epithelium

Departments of ¹Pediatrics, ²Physiology & Biophysics, and ³Molecular Biology & Microbiology, School of Medicine, Case Western Reserve University, Cleveland, Ohio

Submitted 15 April 2008 ; accepted in final form 13 June 2008

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

nuclear factor-B; cytokines; disease models; animal; in vitro; lung diseases; Pseudomonas aeruginosa