Idiopathic pulmonary fibrosis (IPF) is a scarring disease of the lungs for which effective therapy is lacking and which usually progresses to respiratory failure and death within several years. The need to improve outcomes in this devastating disease is therefore urgent, and the single biggest barrier to accomplishing this is the lack of appropriate treatments that can realistically be implemented within the next 5-10 years. Ideally, we would like to have in our therapeutic armamentarium a selection of treatments that: 1) have broad anti-fibrotic actions;2) have an acceptable safety profile;3) are currently available or expected to be available soon;4) could be used alone or in combination with others;and 5) could be applied in a personalized fashion to individual patients, based on in vitro predictors of responsiveness. This proposal capitalizes on 15 years of research by the applicant team which has contributed substantially to current knowledge about two anti-fibrotic substances that meet the above criteria for potential therapies: namely, prostanoids such as prostaglandin Ez (PGE2) and agents such as urokinase that augment the plasminogen activation system. Although PGE2 inhibits virtually all of the functions by which normal lung fibroblasts might contribute to fibrotic lung disease, we have found that fibroblast lines isolated from the majority of individuals with IPF are resistant to the usual suppressive actions of this prostanoid. However, we have identified two distinct molecular mechanisms accounting for such resistance, one of which can be overcome by pretreatment with inhibitors of DNA methylation and the other by pretreatment with urokinase. We thus propose that the in vitro capacity of patient-derived lung fibroblasts to be down-regulated by PGE2, urokinase, methylation inhibitors, or combinations thereof could predict clinical responses to these same regimens. The prospect of imminent feasibility is based on the fact that prostanoids, urokinase, and methylation inhibitors are all currently approved for the treatment of human disease. For these studies we will employ fibroblasts isolated from lung biopsy specimens and from bronchoalveolar lavage of 50 patients with well-characterized IPF participating in our Grand Opportunity COMET study. A panel of potential therapeutic agents, alone and in combination, will be used to treat both cell types in order to determine treatment effects on cellular collagen synthesis and proliferation. Response patterns will be compared for each cell type and will be correlated with clinical progression of disease. In addition, the ability of these same regimens to ameliorate bleomycin-induced pulmonary fibrosis in mice will be assessed. These complementary approaches will determine the most tractable options for ameliorating or halting progression of fibrosis in IPF and will provide a framework for individually tailoring treatment regimens for patients in future clinical trials. The deliverable from CADET I will therefore be a menu of therapies that can be considered for implementation in trials to be proposed in a subsequent CADET II application.

Public Health Relevance

Idiopathic pulmonary fibrosis (IPF) is a lethal scarring disease of the lung for which no effective therapies are currently available. Prostanoids and urokinase oppose lung scarring. This proposal will test the ability of these substances, alone and in combination, to ameliorate scar formation in the lung in both animal models and in cells from patients with IPF. These studies will identify the optimal means of harnessing the anti-fibrotic potential of these substances for future clinical trials in patients with IPF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Specialized Center (P50)
Project #
5P50HL107177-02
Application #
8258723
Study Section
Special Emphasis Panel (ZHL1-CSR-D (F1))
Program Officer
Eu, Jerry Pc
Project Start
2011-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$446,234
Indirect Cost
$159,267
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109