Abstract. Isoform-specific antibodies to TGF01, TGF02, and TGF03 proteins were generated and have been used to examine the expression of these factors in the developing mouse embryo from 12 .5-18 .5 d post coitum (d.p.c.). These studies demonstrate the initial characterization of both TGFs2 and /33 in mammalian embryogenesis and are compared with TGF01. Expression of one or all three TGFO proteins was observed in many tissues, e.g., cartilage, bone, teeth, muscle, heart, blood vessels, lung, kidney, gut, liver, eye, ear, skin, and nervous tissue. Furthermore, all three TGFO proteins demonstrated discrete cell-specific patterns of expression at various stages of development and the wide variety of tissues expressing TGF0 proteins represent all three primary embryonic germ lay-P OLYPEPTIDE growth factors such as the 0-type transforming growth factors (TGFos) mediate many cellcell interactions that occur during embryonic development (reviewed in Mercola and Stiles, 1988;Whitman and Melton, 1989;Nilsen-Hamilton, 1990). Complementary DNA clones havebeen isolated for five TGFS species (TGFos 1-5); however, purified or recombinant protein has been obtained only for TGF$s 1-3 (Derynck et al., 1985(Derynck et al., , 1988Madisen et al., 1988; ten Dijke et al., 1988;Jakowlew et al., 1988). Moreover, only TGFos 1-3 have been found in mammals. The molecular structures of TGF01, (32, and 03 are very similar in that each polypeptide is synthesized as a prepro monomeric protein and is cleaved to yield a 112-amino acid polypeptide that remains associated withthe latent (pro) portion ofthe molecule (reviewed in Lyons and or Miller et al., 1990 . Biologically active TGF0 protein results from dimerization of the monomers (usually homodimers) and release of the latent peptide portion . Overall, the mature region of the TGF03 protein has -80% identity to the mature regions of both TGFO 1 and TGF02, however, the NH2-terminal or precursor regions of these three molecules Melissa Jones' present address is Department of Chemistry, Hendrix College, Conway, AR 72032 .

Evidence suggests that transforming growth factor beta (TGF-beta) may play a central role in a variety of fibroproliferative disorders via the induction of extracellular matrix accumulation. The three mammalian TGF-beta isoforms are present in the normal lung, but very little is known about their expression during lung injury and repair. To more fully understand the role of TGF-beta in lung repair, we investigated the expression of the TGF-beta 1, TGF-beta 2, and TGF-beta 3 isoforms in a bleomycin-induced model of pulmonary fibrosis using immunohistochemical and in situ hybridization techniques. We found expression of the three TGF-beta isoforms, in an identical pattern, widely distributed throughout the normal rat lung: in airways, blood vessels, lung parenchyma, and alveolar macrophages. In general, the distribution of TGF-beta mRNA and protein coincided; however, bronchial epithelial cells were a notable exception, exhibiting immunoreactivity but no mRNA expression. During the "inflammatory" phase (days 1 and 3) of bleomycin-induced injury there was an increase in the mRNA and protein expression of all three TGF-beta isoforms in the injured areas, most prominently in parenchymal cells and alveolar macrophages. There was a further increase in TGF-beta isoform expression in the areas of developing fibrosis during the later reparative phase (days 7 and 14), and the bronchial epithelium, previously not expressing TGF-beta mRNA, showed strong expression of mRNA for the three isoforms concomitant with increased immunoreactivity. These findings implicate the three mammalian TGF-beta isoforms in the dysregulated repair process that results in pulmonary fibrosis. Furthermore, the pattern of TGF-beta mRNA and protein expression by the bronchial epithelium suggests that a transition may occur at this site from a paracrine mode of action in the normal lung to an autocrine mode of action during the "reparative" phase of fibrosis.

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