Localisation of transforming growth factor beta1 and beta3 mRNA transcripts in normal and fibrotic human lung

Abstract

Background-Transforming growth factor 1 is implicated in the pathogenesis of lung fibrosis. It promotes extracellular matrix accumulation by increasing procollagen synthesis and reducing degradation. TGF 1 gene and protein expression increase in experimental lung fibrosis, and TGF 1 antibodies attenuate fibrosis in mice. The role of other TGF isoforms is unclear. This study aimed to localise TGF 1 and TGF 3 gene expression in fibrotic human lung and compare it with that in normal human lung. Methods-Lung tissue from patients with cryptogenic fibrosing alveolitis and fibrosis associated with systemic sclerosis was examined by in situ hybridisation. Macroscopically normal lung from carcinoma resections was used as control tissue. Digoxigenin labelled riboprobes were synthesised from TGF isoform specific cDNA templates. Results-The digoxigenin labelled riboprobes were sensitive and permitted precise cellular localisation of mRNA transcripts. TGF 1 and TGF 3 mRNA transcripts were widespread in normal lung and localised to alveolar macrophages and bronchiolar epithelium. TGF 1 but not TGF 3 mRNA was detected in mesenchymal and endothelial cells. In fibrotic lung tissue mRNA transcripts for both isoforms were also detected in metaplastic type II cells. TGF 1 gene expression was enhanced in some patients. TGF 3 was expressed in fibrotic lung but was not consistently altered compared with controls. Conclusion-TGF 1 mRNA transcripts were localised in normal and fibrotic human lung and TGF 3 gene expression in human lung fibrosis was shown for the first time. The results suggest that TGF 1 may play the predominant role in pathogenesis. It is suggested that TGF 1 should be the primary target of anticytokine treatments for pulmonary fibrosis. (Thorax 2001;56:549-556)

c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis

“…The source of TGF-b in lung tissue and the cells that respond to TGF-b1 during the pathogenesis of tissue fibrosis is unclear, and likely depend on the nature or locale of the insults. Expression of TGF-b occurs in the bronchial epithelium and submucosa of patients with asthma, chronic bronchitis, and fibrosis (42,46). In mice and humans with IPF, the airway epithelium has been suggested to be a major source of TGF-b1 (47,48), although other studies have reported that eosinophils and fibroblasts are a source of TGF-b1 in allergic airway disease (13,49,50).…”

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

“…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). More evidence supporting the hypothesis of TGF-β isoform imbalances in "fibrotic" versus "regular wound healing" can be found in other organ systems.…”

Oxymatrine attenuates bleomycin-induced pulmonary fibrosis in mice via the inhibition of inducible nitric oxide synthase expression and the TGF-β/Smad signaling pathway

“…Previous studies have demonstrated that upregulation of iNOS-induced NO production appears in PF in both animal models and humans (22)(23)(24). Transforming growth factor-β1 (TGF-β1) is well recognized as a key pro-fibrogenetic cytokine in PF, and may result in collagen overproduction and deposition in the lung (25). Elevated expression of TGF-β1 has also been found in the lung tissues of patients and animals with PF (26).…”