This project will determine whether CD40, a member of the TNF receptor superfamily, is a critical element in mediating pulmonary inflammation, dysplasia and fibrosis. The lung is susceptible to damage by treatments for respiratory distress in infants and adults (i.e., oxygen), by therapies for cancer (e.g. chemotherapy) and by exposure to environmental agents (e.g. ozone). Lung damage may induce chronic inflammation, which stimulates fibroblast proliferation and fibrosis. Pulmonary derangement, including bronchopulmonary dysplasia (BPD) in premature infants, is a potentially fetal consequence of severe lung damage. Treatments for pulmonary fibrotic conditions are essentially nonexistent. The fibroblast is the key effector cell responsible for lung fibrosis. T lymphocytes and mast cells are closely associated with lung inflammation and fibrosis and may directly stimulate the fibroblast. The mechanism of interaction between these cells is largely unknown. This laboratory discovered that pulmonary fibroblasts display CD40, a receptor previously thought to be associated with bone marrow derived cells (e.g. B cells). The importance of CD40 is that its ligand (L) is found on T lymphocytes and mast cells and the CD40-CD40L interaction is critical for the stimulation of the CD40 displaying cell. The hypothesis to be tested in this proposal is that CD40 is also a critical regulatory molecule for fibroblasts, important for their proliferation and synthesis of proinflammatory cytokines and collagen. Disruption of the fibroblast CD40 signaling mechanism may inhibit lung inflammation and fibrosis. The significance of fibroblast CD40 for lung inflammation and fibrosis will be determined by answering the following questions as our specific aims. (1) Does CD40 act as a cytokine/growth factor receptor and induce protein tyrosine phosphorylation and fibroblast proliferation? (2) Does crosslinkage of CD40 induce lung fibroblasts to synthesize proinflamatory/profibrotic cytokines and is their production of collagen increased? (3) Does disruption of the CD40-DC40L system in vivo prevent the onset of a BPD-like syndrome in an animal model? Results of this project may lead to the development of new therapeutic strategies to arrest the progression of lung dysplasia in premature infants, and to prevent lung fibrosis in patients' lungs damaged by cancer treatments or environmental agents.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL056002-04
Application #
6184016
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1997-09-01
Project End
2002-08-31
Budget Start
2000-09-01
Budget End
2002-08-31
Support Year
4
Fiscal Year
2000
Total Cost
$228,801
Indirect Cost
Name
University of Rochester
Department
Internal Medicine/Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Koumas, Laura; Phipps, Richard P (2002) Differential COX localization and PG release in Thy-1(+) and Thy-1(-) human female reproductive tract fibroblasts. Am J Physiol Cell Physiol 283:C599-608
Harris, Sarah G; Smith, Roger S; Phipps, Richard P (2002) 15-deoxy-Delta 12,14-PGJ2 induces IL-8 production in human T cells by a mitogen-activated protein kinase pathway. J Immunol 168:1372-9
Padilla, Josue; Leung, Edmund; Phipps, Richard P (2002) Human B lymphocytes and B lymphomas express PPAR-gamma and are killed by PPAR-gamma agonists. Clin Immunol 103:22-33
Harris, Sarah G; Padilla, Josue; Koumas, Laura et al. (2002) Prostaglandins as modulators of immunity. Trends Immunol 23:144-50
Harris, Sarah G; Phipps, Richard P (2002) Prostaglandin D(2), its metabolite 15-d-PGJ(2), and peroxisome proliferator activated receptor-gamma agonists induce apoptosis in transformed, but not normal, human T lineage cells. Immunology 105:23-34
Smith, Roger S; Harris, Sarah G; Phipps, Richard et al. (2002) The Pseudomonas aeruginosa quorum-sensing molecule N-(3-oxododecanoyl)homoserine lactone contributes to virulence and induces inflammation in vivo. J Bacteriol 184:1132-9
Smith, Roger S; Kelly, Rodney; Iglewski, Barbara H et al. (2002) The Pseudomonas autoinducer N-(3-oxododecanoyl) homoserine lactone induces cyclooxygenase-2 and prostaglandin E2 production in human lung fibroblasts: implications for inflammation. J Immunol 169:2636-42
Koumas, Laura; Smith, Terry J; Phipps, Richard P (2002) Fibroblast subsets in the human orbit: Thy-1+ and Thy-1- subpopulations exhibit distinct phenotypes. Eur J Immunol 32:477-85
Phipps, R P; Kaufman, J; Blumberg, N (2001) Platelet derived CD154 (CD40 ligand) and febrile responses to transfusion. Lancet 357:2023-4
Kaufman, J; Graf, B A; Leung, E C et al. (2001) Fibroblasts as sentinel cells: role of the CDcd40-CDcd40 ligand system in fibroblast activation and lung inflammation and fibrosis. Chest 120:53S-55S

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