Increased expression of transforming growth factor beta isoforms (beta 1, beta 2, beta 3) in bleomycin-induced pulmonary fibrosis.
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.
Santana
A
A
Department of Internal Medicine, University of Utah Health Sciences Center, Salt Lake City 84132, USA.
Saxena
B
B
Noble
N A
NA
Gold
L I
LI
Marshall
B C
BC
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D015816:Cell Adhesion Molecules, Neuronal / Q000276:immunology / Q000302:isolation & purification; D016326:Extracellular Matrix Proteins / Q000276:immunology / Q000302:isolation & purification; D005353:Fibronectins / Q000276:immunology / Q000302:isolation & purification; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism*; D015347:RNA Probes; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D019063:Tenascin; D014018:Tissue Distribution; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000145:classification / Q000235:genetics / Q000276:immunology
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D005353:Fibronectins; D015347:RNA Probes; D012333:RNA, Messenger; D019063:Tenascin; D016212:Transforming Growth Factor beta; D001761:Bleomycin