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.
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