Recovery Act Investments in Interstitial Pulmonary Fibrosis

Public Health Burden

Diffuse interstitial pulmonary fibrosis comprises a heterogeneous group of incurable disorders that result in progressive, irreversible destruction of the lung. Idiopathic pulmonary fibrosis (IPF) accounts for about 40% of cases and has an incidence in the United States of 10-40/100,000 adults, a prevalence of about 400,000 cases, and a median survival of three years from diagnosis. No widely effective treatment is available for IPF, but approximately 400 patients per year receive a lung transplant.

Basic Research

Basic research is using animal models of induced pulmonary fibrosis and human IPF lung tissue to uncover new disease mechanisms. Recovery Act-supported research is seeking to determine what causes lung cells to stimulate and perpetuate fibrosis and develop approaches to inhibit the process. This work includes studies to identify agents that suppress or inhibit transforming growth factor (TGF), a cytokine made by certain lung cells; examination of genetic risk factors related to cellular growth pathways; and investigation of ways to facilitate the death of lung cells that cause fibrosis. Projects have been funded to:

• Evaluate the role of vitamin D in regulating TGF and inhibiting its production.¹
• Characterize structural proteins in certain lung cells that can glue together different molecules and may regulate TGF turnover.²
• Investigate pharmacological approaches to inhibit epidermal growth factor receptor (EGFR), a cellular mediator that regulates TGF and other growth factors.³
• Correlate the regulation of EGFR, which induces pulmonary fibrosis, with its genetic variations in a population-based association study.⁴
• Manipulate the regulation of DNA that occurs in the lung fibrosis process to suppress fibrosis in fibroblasts.⁵
• Investigate the excessive production or accumulation of extracellular structural material in IPF and investigate the specific genetic regulation of the disease process.⁶
• Examine cellular signaling pathways that control cell death and fibrosis.⁷
• Investigate genes that control the function of the enzyme telomerase, which can cause fibrosis through its action on chromosomes in lung epithelial cells.⁸

Clinical Research

Recovery Act-supported investigators are evaluating new methods of using genetic analysis and biomarkers contained in blood cells or lung cells to assess the risk of pulmonary fibrosis in persons with a family history of IPF and the rapidity of disease progression. Identifying rapidly progressive IPF will permit earlier treatment decisions including lung transplantation. Approximately 2,000 patients are on the waiting list for lung transplants, but most die before receiving one. Recovery Act funds are being used to:

• Validate a panel of preclinical and symptom-related differences between IPF patients and healthy controls in a large group of patients in order to facilitate early diagnosis and characterization of disease.⁹
• Conduct genome-wide association studies to assess genetic variations that contribute to the risk of developing IPF and predict its severity.¹⁰
• Evaluate biomarkers for predicting rapid progression of IPF in a large group of well-characterized patients to be enrolled in protocols of the NHLBI IPF clinical network.¹¹
• Develop approaches to inactivating inflammatory mediators, such as adenosine, during early ischemia/reperfusion injury in order to mitigate post-transplant injury.¹².
• Investigate the potential for obtaining lungs for transplant from donors whose heart function has ceased.¹³
• Seek to monitor chronic lung graft rejection using gene expression assays and biomarkers of rejection in bronchoalveolar lavage fluid in hopes of improving prediction and diagnosis of lung rejection.^14,15

1. 1 R03 HL097012-01 - Vitamin D Status in Pulmonary Fibrosis - Ramirez, Allan (GA)
2. 1 R03 HL095430-01A1 - Caveolins in the Pathogenesis of Idiopathic Pulmonary Fibrosis - Predescu, Dan N (IL)
3. 3 R01 HL086598-03S1 - Epidermal Growth Factor Receptor Activation in Pulmonary Fibrosis - Hardie, William (OH)
4. 1 R03 HL097016-01 - Genetic Role of EGFR pathway in Interstitial Lung Disease - Liu, Wanqing (IL)
5. 3 R01 HL082818-02S1 - Regulation of Fibroblast Phenotype in Lung Fibrosis - Hagood, James S (AL)
6. 1 R03 HL095411-01A1 - Differentiation of Alveolar Epithelium in Pulmonary Fibrosis - Sannes, Philip L. (NC)
7. 3 R01 HL076340-04S1 - Regulation of Fas-Mediated Lung Cell Apoptosis - Rojanasakul, Yon (WV)
8. 3 R01 HL093096-01A1S1 - Pulmonary Fibrosis and Telomerase Dysfunction - Garcia, Christine Kim (TX)
9. 1 RC1 HL099571-01 - Peripheral Blood Biomarkers for Idiopathic Interstitial Pneumonia - Steele, Mark (NC)
10. 1 RC1 HL099619-01 - Genome-Wide Association and Exon Sequencing Study in IPF - Noth, Imre (IL)
11. 1 RC2 HL101740-01 - CTRIP: Molecular phenotypes of rapidly progressive idiopathic pulmonary fibrosis - Martinez, Fernando J (MI)
12. 3 R01 HL092953-01S1 - Adenosine receptor activation in pulmonary ischemia-reperfusion injury - Kron, Irving (VA)
13. 1 RC2 HL101641-01 - CTRIP Ex-vivo perfusion and ventilation of lungs to assess transplant suitability - Egan, Thomas M. (NC)
14. 3 R01 HL080041-03S1 - Protein Biomarkers in Lung Allograft Rejection - Wendt, Chris H (MN)
15. 1 R01 HL092171-01A1 - Bronchoalveolar Lavage Cell Biomarkers in Lung Rejection - Hertz, Marshall I (MN)

Last Updated April 26, 2010