Presentation: TGF-β Superfamily Members and Cytokine Transcription Factor Genes in Scleroderma Lung Disease (2007)

134 TGF-β Superfamily Members and Cytokine Transcription Factor Genes in Scleroderma Lung Disease


Background: Inflammation, vascular dysfunction, tissue remodeling, and fibrogenesis are hallmark of lung disease in systemic sclerosis (SSc). Whereas type 1 cytokines may trigger inflammation, TGFβ superfamily members and type 2 cytokines are implicated in vascular dysfunction and fibrogenesis. Here, we determined mRNA levels of TGFβ superfamily members, including TGFβ, activin and bone morphogenic protein [BMP], and type 1 and type 2 cytokine transcription factors, including T-bet, STAT4, STAT6 and GATA-3.
Methods: Bronchoalveolar lavage (BAL) samples from 20 patients with alveolitis (neutrophils >3% and/or eosinophils > 2% in the setting of ground glass opacification on HRCT) and 20 without alveolitis (BAL and HRCT negative) were selected at random from the Scleroderma Lung Study. BAL RNA samples were assayed for mRNA levels by reverse transcriptase PCR. Results were expressed as the ratios of band densities of genes tested compared to β-actin.
Results: Among TGFβ system genes, mRNA levels of TGFβ co-receptor ENDOGLIN were markedly elevated in the BAL of patients without alveolitis (p = 0.0003), whereas TGFB1, BGLYCAN, and SMAD3 were not significantly different between the two groups. Amongst other TGFβ superfamily members, BMP2 was elevated in patients without alveolitis (p = 0.04), whereas ACTIVIN was not. Type 1 cytokine transcription factors TBET and STAT4 were not significantly different between the two groups, whereas type 2 cytokine transcription factors STAT6 (p = 0.0002) and GATA3 were elevated by 2-fold in the BAL of patients without alveolitis.
Discussion: We report increased gene expression of TGFβ superfamily members BMP-2 and endoglin and type 2 cytokine transcription factors in the BAL of SSc patients without alveolitis. Our novel observation showing increased gene expression for BMP-2 is particularly significant in the light of our recent finding that protein levels of vascular endothelial growth factor (VEGF) are markedly elevated in SSc patients without alveolitis (Keane, Elashoff, Singh, et al, manuscript in preparation). VEGF has been shown to induce BMP-2 gene expression in endothelial cells. Endoglin has been previously shown to correlate with telangiectasia and vascular remodeling. Taken together, these findings (increased VEGF, BMP-2 and endoglin) suggest an important role of factors that can affect endothelial cell function and cause vascular remodeling during progression of interstitial lung disease beyond alveolitis.
Funding: NIH U01 HL60587, AR055075, AR50797 and AR47322. J.L. is recipient of the Southern California Chapter Scleroderma Foundation fellowship.

 J. Lin, None.