The principal side effect of bleomycin (BLM), an antineoplastic antibiotic, is the induction of pulmonary fibrosis. Using the well established murine model of BLM-induced pulmonary fibrosis, the investigators propose to determine the role of non-T cell cytokines and T-cells in the induction and maintenance of pulmonary fibrosis. Preliminary data of the investigators indicate that BLM induces pulmonary fibrosis in C57BL/6 mice lacking B and T cells (SCID mice) and (C57BL/6 SCID X CB.17 SCID) F1 mice but not in CB.17 SCID mice. Recently, the investigators demonstrated that C57BL/6 mice in which pulmonary fibrosis was induced with intratracheal (i.t.) BLM exhibited marked systemic suppression in their ability to generate anti-sheep erythrocyte plaque-forming cell responses. Immunosuppression was not caused by BLM per se and was a general consequence of fibrosis and was independent of the method by which fibrosis was induced. The unifying hypothesis of this proposal is that underlying cytokine-mediated events induced by BLM initiate pulmonary fibrosis and are also responsible for the immunosuppression that is associated with the disorder.
The aims are: 1) To investigate the role of T cell and non-T cell cytokines in initiating and maintaining bleomycin (BLM)-induced pulmonary fibrosis in mice. SCID mice and their euthymic counterparts will be used to determine the non-T cell cytokines which are important for the development of fibrosis and to differentiate the non-T cell mediated from the T cell associated components of the disease. The role of BLM-induced reactive oxygen intermediates in regulation of early profibrogenic cytokines will be analyzed and mice resistant to BLM-induced fibrosis will be manipulated to make them BLM-susceptible so as to be able to identify the early cytokine events involved in BLM-sensitivity. 2) To determine the basis of immunosuppression that is seen in BLM-induced pulmonary fibrosis. The hypothesis that BLM-induced alterations in the balance between Th1 and Th2 helper T cell populations is at least in part responsible for immunosuppression will be tested. Since TGF-b, NO and IFN-g are induced during BLM initiated pulmonary fibrosis and these products have been shown to be immunosuppressive they will serve as starting points to investigate the mechanism of immunosuppression.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL058058-02
Application #
2901298
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1998-04-01
Project End
2001-03-31
Budget Start
1999-04-01
Budget End
2000-03-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Lexington
State
KY
Country
United States
Zip Code
40506
Avdiushko, R; Hongo, D; Lake-Bullock, H et al. (2001) IL-10 receptor dysfunction in macrophages during chronic inflammation. J Leukoc Biol 70:624-32