Increased expression of transforming growth factor beta isoforms (beta 1, beta 2, beta 3) in bleomycin-induced pulmonary fibrosis.

Abstract

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.

Progressive pulmonary fibrosis is mediated by TGF-β isoform 1 but not TGF-β3

“…Earlier experiments investigating alveolar macrophages from bleomycin-treated rats have also shown that these cells secrete TGF-β1, but not TGF-β2 or -β3 (Khalil, Shing et al, 1993;Khalil, Whitman, Zuo, Danielpour, & Greenberg, 1993). Another group failed to show differences in the expression of TGF-β isoforms after bleomycin (Santana et al, 1995). So far, only two studies have analyzed TGF-β3 expression in fibrotic human lung tissue, and both supported a more prominent role for TGF-β1 compared with TGF-β3 (Coker et al, 2001;Khalil et al, 1996).…”

“…Most studies thus far have focussed on the most prominent isoform, TGF-β1, and demonstrated an array of profibrotic functions. Only a limited number of studies have specifically addressed the role of TGF-β3 in the pathogenesis of wound healing and fibrosis (Khalil, O'Connor, Flanders, & Unruh, 1996;Khalil et al, 2001;Santana et al, 1995;Shah et al, 1995). While some of these studies assigned no major individual role to TGF-β3, there is also evidence for distinct and specific features of TGF-β3 that even suggest potential anti-scarring properties.…”

“…Moreover, the balance amongst the TGF-β1 and TGF-β3 isoforms is a neglected, but important component in the process of tissue repair. Some of these studies supported no major individual role, and claimed that TGF-β3 acts in concert with TGF-β1 (Eickelberg et al, 1999;Khalil, Shing, & Whitman, 1993;Santana, Saxena, Noble, Gold, & Marshall, 1995). In contrast, data from targeted gene knockouts and experimental models of cutaneous wound healing and chronic inflammatory bowel disease suggested distinct features of TGF-β3, when compared with TGF-β1 (Ingman & Robertson, 2002;McKaig, Hughes, Tighe, & Mahida, 2002;Shah, Foreman, & Ferguson, 1995;Van Themsche, Mathieu, Parent, & Asselin, 2007).…”

Dietary riboflavin deficiency decreases immunity and antioxidant capacity, and changes tight junction proteins and related signaling molecules mRNA expression in the gills of young grass carp (Ctenopharyngodon idella)

“…It was reported that the up-regulation of pro-inflammatory cytokines, such as IL-8, TNF-a, IFN-g and IL-1b [61,62], and the downregulation of anti-inflammatory cytokines, such as IL-10 and TGFb [63,64] initiated inflammatory process. In this study, compared with optimal riboflavin supplementation, riboflavin deficiency increased pro-inflammatory cytokines IL-1b, IL-8, IFN-g2 and TNFa mRNA levels, and decreased anti-inflammatory cytokines IL-10 and TGF-b1 mRNA levels in the gills of young grass carp (Fig.…”

The TNF−α –308, MCP−1 –2518 and TGF−β1 +915 polymorphisms are not associated with the development of chronic lung disease in very low birth weight infants

“…Increased expression of TGF-b 1 has been implicated in the development of lung fibrosis in both animal models and human disease. [16][17][18] A role for TGF-b 1 in the development of CLD in the preterm newborn is suggested by the finding of increased concentrations in TA fluid of infants who develop this complication. 7 Several polymorphisms have been described for the TGF-b 1 gene.…”