Patients with cystic fibrosis (CF) have a defect in a single gene that encodes a cAMP-regulated chloride channel, but most patients die of lung infection and inflammation. The inflammatory response to the most common infecting organism in CF, Pseudomonas aeruginosa, is excessive in patients, mouse models of CF, and airway epithelial cells of CF phenotype compared to matched controls. Inflammation in the CF lung is important not only because it causes much morbidity and mortality, but also because it represents an excellent, underutilized, therapeutic target. Treatment with high dose ibuprofen markedly retards progression of the lung disease, but this drug is often not used for fear of rare, but severe, adverse effects. The causes of the excessive inflammatory response in CF are multifactorial, but there is failure to properly down regulate the initial inflammatory response. One counter-regulatory influence on the inflammatory response is the peroxisome proliferation activator receptor (PPAR), the form of which is expressed in airway epithelium. Activation of PPAR- by binding to a ligand permits heterodimerization with the retinoid X receptor, DNA binding, and transcriptional regulation. Recently, ibuprofen, in concentrations achieved in CF, has been shown to bind to PPAR- and activate it. Preliminary data indicate that PPAR is expressed in non-CF and CF phenotype airway epithelial cells, but its degree of activation is less in the CF cells, both in the basal state and following stimulation with P. aeruginosa. In addition, ibuprofen, in concentrations achieved in CF p atients, activates PPAR. Ibuprofen causes reduction of proinflammatory cytokme production, release of matrix metalloproteinase-9, and AP-1-regulated transcription. We propose to test whether PPAR participates in limiting the inflammatoryresponse in airway epithelial cells and in the lungs of mice, to determine whether PPAR- activation is indeed reduced in CF airway epithelium and whether this contributes to the excess inflammmatoryresponse in CF, and to determine whether PPAR ligands other than ibuprofen are candidate therapeutic agents for the CF lung disease. If these studies are accomplished, the result will be improved understanding of regulation of the inflammatory response in airways and the pathobiology of the excess inflammation in CF, identification of a possible major mechanism by which ibuprofen exerts its therapeutic effect in CF, and identification of alternative therapeutic agents which might substitute for ibuprofen and have more favorable perceived therapeutic index. Such treatment has the potential to alter the rate of decline of lung function in CF and thereby to prolong life. PERFORMANCE S JE(S)(organization, city, state) Case Western Reserve University Cleveland, OH 44106 KEY PERSONNEL.See instructions. Use continuation pages as neededto provide the required information in the format shown below. Start with Principal Investigator. List all other key personnel in alphabetical order, last name first. Name Organization Role on Project Pamela B. Davis Case Western Reserve University Principal Investigator Dianne Kube Case Western Reserve University Sr. Research Associate Anna van Heeckeren Case Western Reserve University Sr. Research Associate Disclosure Permission Sfafemenf.Applicable to SBIR/STTR Onlv.See Instructions. LH Yes CD No PHS 398 (Rev.05/01) Page 2 Form Page 2 Principal Investigator/Program Director (Last, first, middle): Davis, Pamela B. The name of the principal investigator/program director must be provided at the top of each printed page and each continuation page. RESEARCH GRANT TABLE OF CONTENTS PageNumbers Face Page ' Description,
| Hsu, Daniel; Taylor, Patricia; Fletcher, Dave et al. (2016) Interleukin-17 Pathophysiology and Therapeutic Intervention in Cystic Fibrosis Lung Infection and Inflammation. Infect Immun 84:2410-21 |
| Perez, Aura; van Heeckeren, Anna M; Nichols, David et al. (2008) Peroxisome proliferator-activated receptor-gamma in cystic fibrosis lung epithelium. Am J Physiol Lung Cell Mol Physiol 295:L303-13 |
| Davis, Pamela B (2006) Cystic fibrosis since 1938. Am J Respir Crit Care Med 173:475-82 |
