The hapten immune pulmonary interstitial fibrosis or HIPIF is an experimental system for pulmonary interstitial fibrosis (PlF) induced by a single immunological challenge in the lungs of hapten-immune animals. The HIPIF system is novel and demonstrates, for the first time, the possibility that mechanisms such as those involved in allergic contact dermatitis may contribute to lung disease. Thus, these studies deal with a model for environmental toxins that induce lung and skin disease. We propose the hypothesis that cell mediated immune mechanisms induce and regulate non-resolving fibrosis in hapten-immune and challenged mice. The observation that the ability to develop HIPIF is associated with the genetic ability of the strain to respond to the immunizing hapten with a delayed type hypersensitivity response will be studied in mice. Within the system is a challenged-only control group that represents a lung injury model of fibrosis. We will determine the regulatory factors that influence or promote the immune fibrotic lesion as compared to the lesion seen in the toxic control (challenged-only). Comparisons of responses also will be made between two contact sensitizers which are not equal in their capacity to induce fibrosis (TNP>DNP). A description of the subsets of lymphocytes, macrophages, and fibroblasts that accumulate in the lungs of the various treatment groups of mice will be performed. These subsets will be defined both by cell surface molecular phenotype and by cytokine mRNA profile. T cells within the pulmonary lymphoid tissues will be analyzed by limit dilution analysis to determine cytotoxic T cell precursor frequency. In an effort to study unique aspects of T lymphocyte response and antigen presenting cell peculiarities within the lung T cell clones and hybridomas will be generated. Functional and antigenic assays will be used to define both associated bioactivities and presence of cytokines in lavage fluid and culture supernatants of subpopulations of lung mononuclear cells harvested from mouse lungs and hilar lymph nodes in the various treatment groups. Antibody knockout studies will help determine the role of cytokines in vivo. The fibrosis will be defined by the amount of hydroxyproline (collagen) that is deposited both in vivo and in vitro cultures of fibroblasts harvested from the treatment groups as well as with morphologic studies using collagen specific stains. Careful selection of unique phenomenon in each paradigm will help to dissect the regulation of immune versus toxic mediated pulmonary fibrosis. In this way, we will study the mechanism that might be used by environmental toxins (small reactive chemicals) in the induction of pulmonary interstitial fibrosis and their relationship to delayed type hypersensitivity responses in the lung as well as the skin.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL033709-07A4
Application #
2217312
Study Section
Lung Biology and Pathology Study Section (LBPA)
Project Start
1984-07-01
Project End
1997-05-31
Budget Start
1994-07-01
Budget End
1995-05-31
Support Year
7
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Zhang-Hoover, J; Sutton, A; Stein-Streilein, J (2001) CD40/CD40 ligand interactions are critical for elicitation of autoimmune-mediated fibrosis in the lung. J Immunol 166:3556-63
Stein-Streilein, J; Sonoda, K H; Faunce, D et al. (2000) Regulation of adaptive immune responses by innate cells expressing NK markers and antigen-transporting macrophages. J Leukoc Biol 67:488-94
Asea, A; Stein-Streilein, J (1998) Signalling through NK1.1 triggers NK cells to die but induces NK T cells to produce interleukin-4. Immunology 93:296-305
D'Orazio, J A; Cole, B C; Stein-Streilein, J (1996) Mycoplasma arthritidis mitogen up-regulates human NK cell activity. Infect Immun 64:441-7
Hu, H; Stein-Streilein, J (1993) Hapten-immune pulmonary interstitial fibrosis (HIPIF) in mice requires both CD4+ and CD8+ T lymphocytes. J Leukoc Biol 54:414-22
Stein-Streilein, J; Salter-Cid, L; Roberts, B et al. (1992) Persistent pulmonary interstitial fibrosis, induced by immune response to TNP, is associated with altered mRNA procollagen type I:III ratio. Reg Immunol 4:391-400
Kimura, R; Hu, H; Stein-Streilein, J (1992) Delayed-type hypersensitivity responses regulate collagen deposition in the lung. Immunology 77:550-5
Kimura, R; Hu, H; Stein-Streilein, J (1992) Immunological tolerance to hapten prevents subsequent induction of hapten-immune pulmonary interstitial fibrosis (HIPIF). Cell Immunol 145:351-8
Garcia, H; Salter-Cid, L; Stein-Streilein, J (1992) Persistent interleukin-2 activity and molecular evidence for expression of lymphotoxin in the hapten-immune model for pulmonary interstitial fibrosis. Am J Respir Cell Mol Biol 6:22-8
Peacock, J S; Tan, J; Guffee, J et al. (1991) Monovalent Fab fragments of D7.5 monoclonal antibody activate intracellular Ca2+ mobilization and secretion of cytolytic factors by thymus cells. J Leukoc Biol 49:90-7

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