PULMONARY INTERTITIAL DISEASE BY HAPTENS

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The purpose of this proposal is to study the expression of hypersensitivity in the lung using simple chemicals (2, 4, 6, trinitro-l-chlorobenzene, TNCB; Dinitrofluorobenezene, DNFB). Haptens used in the studies are similar to chemicals (trimellitic anhydride, TMA) described as industrial hazards of workers in the plastics industry. The studies are directed toward the analysis to experimental models for pulmonary interstitial disease that have been developed by the Principal Investigator. The results of these studies will have relevance for understanding mechanisms for pulmonary disease caused by industrial or environmental chemicals that react like haptens. The animals will be primed with hapten via the skin and a pulmonary response will be elicited by intratracheal inoculation of the immunizing chemical. The reactions will be assayed by histological examination of lung tissue sections, by differential analysis of cells from lung lavage, and importantly by biochemical parameters associated with other models of pulmonary interstitital fibrosis. Two pulmonary reactions have been described. An early toxic lesion as well as a late lesion demonstrating fibrotic changes was observed in (hamster) lungs 15-21 days after challenge. Pulmonary immune responses will be studied in various lymphoid compartments of the lung. The systemic immune system will be studies by quantitating specific T-lymphocytes with proliferation, and delayed type hypersensitivity and cytotoxic cell assays as well as quantitating serum antibody and specific antibody forming cells (AFC). The relationship of augmented natural killer cell activity to the pulmonary disease will be considered. The results from these studies will give new insights into the immune mechanisms that participate in the etiology of pulmonary interstitial disease. Non immune mechanisms of the experimental (hapten induced) lung disease will be determined by developing a biochemical definition of the pulmonary lesion. Preliminary studies have demonstrated an increase in total lung collagen as well as an increase in the amount of crosslinking molecules per mole of collagen in experimental hamster when compared to challenge only or normal animals. Data has also been collected that records as increase in elastin in the lungs of experimental hamsters (two weeks post challenge) compared to control animals. A biochemical analysis of this pulmonary lesion that can be induced by a severe immunological challenge in immune animals will complement the histological studies and may broaden our understanding of the development of fibrosis in the lung in general.