Eosinophils have been associated with fibrosis. To investigate their direct role in fibrosis, human peripheral blood eosinophil sonicate was added to human lung or dermal fibroblasts, and proliferation ([ 3 H]thymidine) and collagen synthesis ([ 3 H]proline) were evaluated. Proliferation was enhanced significantly in the monolayers in a dosedependent manner. The activity of the eosinophil fibrogenic factor(s) remained unaltered when heated (56°C, 30 min). Supernatants of cultured eosinophils (20 min or 18 hr) also enhanced lung fibroblast proliferation, indicating that the preformed mitogenic factor(s) can be released both promptly and with a long kinetic. Eosinophils significantly decreased collagen production in lung fibroblasts while increasing it in dermal fibroblasts. However, eosinophils containing matrix metalloproteinase 9 (zymography) in latent form and tissue inhibitors of metalloproteinases 1 and 2 (reverse zymography) did not inf luence either fibroblast matrix metalloproteinases or tissue inhibitors of metalloproteinases. Eosinophil sonicate added to skin and lung fibroblasts in tridimensional collagen lattices significantly enhanced lattice contraction. Transforming growth factor ␤ (TGF-␤) is a major fibrogenic cytokine produced by eosinophils. Therefore, to assess its role, eosinophil sonicate was preincubated with anti-TGF-␤ neutralizing antibodies. This treatment partially inhibited proliferation of lung and collagen synthesis of dermal fibroblasts and suppressed the stimulation of lattice contraction, indicating the fibrogenic role of eosinophil-associated TGF-␤. In conclusion, we have shown that eosinophils act as direct modulatory cells in fibroblast proliferation, collagen synthesis, and lattice contraction, in part, through TGF-␤. These data corroborate the importance of eosinophils in skin and lung fibrosis.

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This paper describes an interactive system for proving theorems in the first order predicate calculus. The system utilizes Jeffrey' s tree method, a variant of Beth's method of semantic tableaux, which lends itself well to a man-machine interactive type of implementation. The method also permits one to separate clearly the basic problems involved in automatic theorem proving from those of devising suitable heuristics to obtain a proof. The latter can be superimposed on the basic system at a later stage by means of a strategy language. This paper places special emphasis on a detailed description of programs involved. The system is operational on a small computer.

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